International Elsevier
CARD10
Journal of Cardiology,
29 (1990) 113-119
113
01146
Editorial
The gender gap: why do women live longer than men? Stephen Department
of Cardiology,
Seely
University of Manchester,
U.K. The Royal Infirmary, Manchester,
V. K.
(Received 19 January 1990; revision accepted 27 June 1990)
Seely S. The gender
gap: why do women
live longer
than men? Int J Cardiol
1990;29:113-119.
In countries for which statistics are available, women outlive men by about 6 years. In developing countries the female advantage for survival - the gender gap - is probably less. It was also smaller in advanced countries in the past. For instance, it was only 2 years in the United States in 1920. The question is why women can derive a greater benefit than men from the changed living conditions associated with prosperity. In general terms, the suggested answer is that humanity is now in a transitional state between conditions when the greatest danger to life was starvation, and one in which that is superseded by surfeit and overnutrition. We are only beginning to realize that overabundance also has its hazards - the prosperity-related diseases. Women are better able to cope with overnutrition than men because they always had to mobilise stores of nutrients in the body for the purposes of procreation. The means used for mobilisation of such stores provides them with better facilities for the excretion of unwanted nutrients. Key words:
Lipid;
Arterial
disease;
Epidemiology
Introduction The gender gap is the difference between male and female expectation of life at birth, generally of the order of 6 years in favour of women in countries for which statistics are available. Table 1 shows data for 27 countries. The average in these countries is 6.4 years, ranging from 3.4 years in Cuba to 8.7 years in the U.S.S.R. Generally, the gender gap tends to increase with prosperity. In third-world countries it is probably low, as it was probably low in all countries in the past. Thus, in
Correspondence to: Dr. S. Seely, Dept. of Cardiology. The Royal Infirmary, Manchester, Ml3 9WL, U.K. 0167-5273/90/$03.50
1920, the gender gap was only 2 years in the United States, against its present value of 7.2 years. The correlation between the gender gap and prosperity, nonetheless, or between the gender gap and the average expectation of life for men and women, is irregular. Thus, the average expectation of life is currently highest in Japan at 79 years, where the gender gap, 6.2 years, is slightly below the average. In the U.S.S.R., the average expectation of life for both sexes is 69 years, with a gender gap of 8.7 years. Why do women live longer than men, and what is the reason for the gradual increase of the gender gap in the course of the present century? This paper takes a brief look at the problem and discusses some past ideas as well as possible lines of inquiry for future research.
0 1990 Else3ier Science Publishers B.V. (Biomedical Division)
114
Is there a general female advantage for survival? Some authors [1,2] believe that a female advantage for survival already exists in animals. Others [3] dispute this, and also point out that longevity in animals has little relevance to human lifespan. Wild animals do not reach their lifespan potential. Laboratory animals allowed to live under sheltered conditions do not die of the same diseases as we do. Thus, the chief cause of death in old laboratory rats is kidney failure - an infrequent cause of mortality in humans. Mortality statistics show that women are not less vulnerable than men to all diseases. In a few
TABLE
1
The gender gap in selected countries. Country
Date of statistics
Expectation of life Gender at birth, years gap (years) Male Female
Austria Belgium Denmark Finland France East Germany West Germany Hungary Italy The Netherl. Norway Portugal Spain Sweden Switzerland U.K. U.S.S.R. Canada Cuba Mexico U.S.A. Israel Japan Kuwait Sri Lanka Australia New Zealand
1987 1986 1986 1986 1986 1987 1987 1987 1985 1986 1986 1987 1984 1986 1987 1987 1986 1986 1986 1983 1986 1986 1987 1987 1983 1986 1986
71.6 70.9 71.9 70.6 71.8 69.9 72.2 65.7 72.2 73.1 72.9 70.6 73.2 74.0 74.0 72.4 65.1 73.1 72.7 65.8 71.4 73.4 75.9 72.5 66.6 73.0 71.1
78.2 77.7 77.8 78.9 80.0 76.0 78.9 73.9 78.8 79.8 79.9 77.5 79.8 80.2 81.0 78.3 73.8 79.9 76.1 71.6 78.6 77.0 82.1 75.8 71.6 79.6 77.5
6.6 6.8 5.9 8.3 8.2 6.1 6.7 8.2 6.6 6.7 7.0 6.9 6.6 6.2 7.0 5.9 8.7 6.8 3.4 5.8 7.2 3.6 6.2 3.3 4.8 6.6 6.4
Extracted from World Health Statistics Annual 1988, Geneva, 1988.
cases, female mortality is higher. Primary pulmonary hypertension and multiple sclerosis are two examples. The combined death rate from cancer of the breast, uterus and cervix is higher than from the corresponding causes, cancer of the prostate and testes, in men. Table 2 shows mortality rates for males and females in the age group from 65 to 74 from selected causes in a few countries. Generally, however, men die from most diseases at an earlier average age than do women. The most important disorders where women have a pronounced advantage for survival are arterial disease and some types of cancer, such as those of the digestive tract. Men are also more vulnerable to self-inflicted hazards, like smoking, and more die of accidents and violence. Male mortality from cancer of the lung, for instance, exceeds female mortality in the three countries shown in Table 2 by a factor ranging from 2.8 to 4.1. This is the presumable explanation of the low gender gap found in studies on 7th Day Adventists [4,5], who abstain from the consumption of alcohol and coffee, and are non-smokers. The gender gap probably springs from two roots. One is the apparent ability of women to derive a greater benefit from prosperity-related changes in living conditions. But, beside this, it seems unavoidable to assume some basic biological advantage for females in terms of survival. This advantage seems to apply to many diseases, so that the understanding of its causes needs the concerted efforts of specialists in many fields. The present paper is intended to discuss only the possible reasons for lower female mortality from arterial disease.
Possible causes of lower female mortality from arterial disease Sex hormones
When the problem began to be considered why men were more vulnerable than women to arterial disease, one of the early ideas was that oestrogens had a protective effect on the arteries. The assumption was thought to be supported by the rapid increase in female cardiovascular mortality
115 TABLE
2
Male and female mortality 198661987.
rates in the 65-74
Cause of mortality
age group
U.S., 1986 Male
Cancer of the breast, uterus and cervix Cancer of the prostate Cancer of the lung Cancer, total Coronary disease (acute myocardial infarction and other ischaemic heart disease) Cerebrovascular disease Multiple sclerosis Male/female mortality ratio Cancer, total Coronary Cerebrovascular Abstracted
from selected
England Female
1110.8 197.8 1.7
Health
Female
Statistics
Annuals,
England
Japan,
and Wales and Japan
146.4 644.6
514.1 150.5 2.0
1489.1 359.2 4.7
Female
43.6
154.8 752.9
23.6 229.7 1014.7
55.4 451.6
661 .o 274.2 6.2
192.5 369.3 4.1
96.5 234.4 6.5
1.71 2.25 1.31
in
1987
Male
170.9 109.1 496.4 1287.0
1.68 2.16 1.31
States,
and Wales. 1987
Male
138.9 107.3 407.5 1085.6
disease
from World
causes in the United
2.25 1.99 1.58
1989.
after the menopause, as if the decrease in the serum level of oestrogens at that time had attenuated some protective mechanism. This was the basis of the Coronary Drug Project [6], in which oestrogens were administered to male patients with coronary arterial disease in the hope that life would be prolonged. The result of this trial, as well as that of another trial initiated by the Veterans Administration [7], in which prostatic cancer patients were treated with oestrogens, demonstrated that these had an adverse effect on the arteries, increasing mortality from both coronary arterial and cerebrovascular disease in the treated group in comparison with controls. The ill-effects were so pronounced that, in the 196Os, medical opinion swung in the opposite direction, casting oestrogens in the role of pathogenic agents instead of remedies [g]. Recently, Luria [9] has surveyed the large volume of literature on the subject, concluding that the preoccupation with oestrogens has produced few useful results. Given large doses, oestrogens are harmful, probably acting as clotting agents, but under normal conditions they do not constitute an important risk factor of atherogenesis. Small-scale trials have also been conducted on the effect of testosterone on patients with coronary
arterial disease [lO,ll]. Apart from some unwanted androgenic effects, beneficial results were claimed for it, and work on modified steroids which would retain the useful features without the androgenic effects still continues. High-density lipoproteins The best-known differences between the male and female circulatory system which is likely to have a bearing on arterial disease is the greater concentration of high-density liproteins in the plasma of women: about 0.6 g/l in comparison with 0.45 g/l in male plasma. As these proteins carry cholesterol from peripheral tissues, and possibly from atheromatous plaques, to the liver for re-use or excretion, they probably play a significant part in the prevention or slowing down of the atherogenetic process. A large volume of literature is available on the subject. It is not intended to review it in detail. The presumed biological reason for the greater concentration of high-density lipoproteins in the plasma of women is the necessity of transferring nutrients from the maternal to the fetal circulation in pregnancy. Cholesterol is an essential component of cell membranes. The need for it in a
116
continuously proliferating cell community is greater than in the adult body. There is, indeed, an increase of the concentration of lipoproteins both of high and low density - in the female circulation during pregnancy [ 121, indicating increased activity in both the synthesis of cholesterol and in its mobilisation from existing stores. The interaction of the maternal and fetal circulations is through the chorionic villi, the action of which is essentially similar to that of the intestinal villi of adults. They can exercise a degree of selection, concentrating some substances and rejecting others. While the need for a greater concentration of high-density lipoproteins arises mainly in pregnancy, women always maintain a higher store of them than men. This probably serves them well in the disposal of excess cholesterol at any time.
Calcium metabolism A similar, but less appreciated, difference could arise in connexion with the transfer of calcium (and possibly other minerals and trace elements) from the maternal to the fetal circulation in pregnancy, and from the mother to the offspring in lactation. This section is an attempt to explain why such transfer may represent a female advantage for survival. The diet of advanced countries includes an unnatural food - milk - not consumed by an adult animal except man. Nature designed milk for the needs of infants, whose growing skeleton needs more calcium in proportion to body weight than the adult body. Furthermore, various animals grow at a different rate. The human infant grows comparatively slowly; a calf, in contrast, reaches its adult size in 3 years, 5 or 6 times more quickly. Cow’s milk caters for their need, not for that of human adults. The body of a 70 kg adult male contains about 1.2 kg calcium, 99% of which is in the skeleton. The remaining 1% plays an essential part in many biological processes, like muscular contraction, which, however, do not consume calcium. Thus, in muscular contraction, calcium ions are released from the endoplasmic reticulum of muscles. They
trigger off contraction, after which they are actively withdrawn for further storage into the endoplasmic reticulum. Once the skeleton is at its maximum adult size, and the storage depots in body fluids, nerves, muscles, and so on are established, the need for calcium of the adult male body is nil, and that of the female body arises only in pregnancy or lactation. Zero consumption does not mean that the dietary intake could also be reduced to zero. Calcium is excreted by the kidneys, sweat glands and the liver. If calcium intake is too high, the kidneys have to do extra work by concentrating it in the urine. If it is too low, they have to do work to conserve it. The optimal intake is presumably that which minimizes the work of the kidneys, namely when the urine is isotonic with blood in respect of concentration of calcium ions. The human skeleton reaches its maximum size and weight at the age of about 35. It remains at this size for only about lo-12 years, after which time it begins to shrink. After the late forties, calcium released from the decreasing skeleton is added to a possibly already excessive dietary intake. At the same time, hard physical exertion is likely to become less frequent, reducing the amount of calcium lost in sweat. This may be the time when the excretory mechanism is unable to cope with its load and calcium excess becomes a hazard. The excess may be deposited in soft tissues, notably in arteries. The elasticity of the aorta is an essential requirement in the functioning of the circulatory system, because the energy stored in its distended elastic walls is needed for the maintenance of diastolic pressure. As it loses elasticity, an increasingly high systolic pressure is needed to maintain diastolic pressure at a given value [13]. The aorta and other large arteries gradually lose elasticity throughout life [14,15], in men at a higher rate than in premenopausal women.. After the menopause, the rate of stiffening of the female aorta increases and gradually becomes comparable with the male aorta. This process, which will be mentioned again in the next section, is multicausal, but the effects are additive. The calcification of the aorta is the last stage in the process and is a predictor of cardiovascular mortality [16].
117
It may be pointed out that metabolism of calcium is a complex process, involving hormonal control and the presence of vitamin D for internal transport. Proteinaceous foods apparently facilitate the uptake of calcium from the intestines, others inhibit it. The fact remains that, in old age, several of these factors become confluent to result in the calcification of soft tissues. In advanced countries, up to 80% of the dietary intake of calcium may come from milk and dairy products. Apart from the already outlined physiological causes, the strong statistical correlation between consumption of milk and death froin coronary arterial disease [17] draws attention to the possibility that the daily intake of calcium, regarded normal by nutritionists at 600-1000 mg per day is, in fact, excessive. There are no signs of calcium deficiency in countries where the calcium intake is around 400 mg/day. The average woman in advanced countries gives birth to two children. During pregnancy and, when it applies, during the subsequent period of lactation, the usual process of calcium accumulation may be at a standstill, or may even be reversed, by calcium being withdrawn from the skeleton. In addition, as will be discussed later, menstruation may play a part in the regulation of micronutrients, like calcium, representing a factor in female advantage for survival. Iron metabolism
and haematocrit
The adult human body contains 4-5 g of iron, about 70% of which is in haemoglobin. The rest is protein-bound, mainly in large ferritin molecules, possibly as a reserve for haemoglobin. The turnover of iron in the body is minimal. When red blood cells die, their content of haemoglobin is transferred to nascent blood cells. Urine contains only a minute amount of iron. There is no true excretory pathway for iron: the main regulatory mechanism is the control of its absorption from the intestines. The body possesses various mechanisms for the excretion of substances which present difficulties for the normal excretory channel. Arsenic, for instance, is incorporated into hairs and nails, and is eliminated as they grow out of the body. In
other cases some cells scavenge pathogenic matter and work their way out of the body, carrying the pathogens with them. When the need arises, this method is used in the case of iron. Cells of the intestinal mucosa, laden with ferritin, are sloughed into the intestines. Menstruation may represent a similar pathway. Women in their reproductive period may absorb more iron and other micronutrients in the anticipation of pregnancy than their normal needs. If pregnancy does not follow, they excrete this material in menstrual bleeding. Medical science has paid little attention to the possible function of menstruation, even if some authors do take up the matter [18]. I suggested some years ago [19] that its function was excretory. Apart from iron, menstrual cycling may play a part in the regulation of various minerals, like magnesium and zinc [20]. Beside bleeding, menstrual cycling appears to involve bouts of sweating [21], with a possible effect on calcium excretion. Whatever the exact mechanism may be, it appears that women age more slowly than men while menstrual periods last, but lose this advantage after the menopause. The control of the uptake of iron from the intestine is faulty in some individuals. From such cases the toxic and carcinogenic effect of excess iron on the liver, pancreas and other organs is well known. Kon [22], however, suggests that the minute amounts of iron in body fluids play an important part in the aging process even in normal individuals. Iron finds its way into all tissues and acts as an oxidising agent, causing the oxidative cross-linking of protein fibres. This is a recognised cause of the loss of elasticity and gradually increasing rigidity in soft tissues. The possibility, therefore, exists that a regular removal of surplus iron in menstrual bleeding has a beneficial effect on the aging process, and represents another instance of female survival advantage. Another difference between the two sexes is the lower haematocrit of women. The normal volume of packed red cells is about 0.45 l/l in men, 0.41 l/l in women. The haematocrit is an important determinant of the viscosity and flow properties of blood, sometimes of critical significance in narrowed arteries.
118
No satisfactory explanation exists for the higher haematocrit of men. Dormandy [23] suggest that the human haematocrit is higher than its optimal value. At least on some occasions the oxygencarrying capacity of blood can be improved by haemodilution, the modern equivalent of the time-honoured practice of bloodletting, because the gain from increased blood flow, resulting from lower viscosity, is greater than the loss from a lower proportion of haemoglobin in the blood. According to Dormandy [23], the present level of haematocrit might have been optimal in the past, when the risk of blood loss from injuries was greater, but the evolutionary process has so far failed to respond to changing environmental conditions. The problem of the higher male haematocrit is an intriguing one. Beside the possibility suggested by Dormandy [23] that it might be useful in the case of injuries, its conceivable function could be higher endurance. It is interesting to note, in this connexion, the great variety of haemoglobin-like iron proteins in invertebrates, with atomic weights ranging from 17,000 to 1,275,OOO. The largest of these erythrocruorins are thought to serve as stores for oxygen, presumably for emergencies, not transport. The aim of having an oxygen reserve in the body seems to have deep roots in evolutionary history, and the higher than optimal haematocrit of men may be another example of this trend. Be this as it may, the high male haemotocrit seems to have a negative value, for survival under present conditions. It might be mentioned that the human circulatory system is the target organ of a legion of plant toxins [24,25]. For instance haemagglutinins which can cause aggregation of red cells and greatly increase blood viscosity, are produced by a host of plants: beans, peas, lentils, cereals, potatoes, peanuts, bananas. All these hazards suggest that a haematocrit erring on the low side is now more conducive to longevity than one on the high side.
terrestrial life, the danger of starvation and malnutrition has been removed from at least some human communities, and was superseded by that of overnutrition. The result of the excess intake of macronutrients, coupled with the natural thrift of the body always prepared for possible periods of starvation, is obvious enough in overweight individuals. The less appreciated hazard is that when the same thing happens with micronutrients, like calcium and iron, there are no immediate signs of unwanted accumulations. Nevertheless, such minerals in excess may play a major part in the pathogenesis of some prosperity-related disorders, like arterial disease. The female advantage for survival may arise in prosperous countries by the innate ability of the female body to mobilise and transport nutrients for the benefit of the fetus in pregnancy. Apart from the quantity of nutrients transferred to the fetus, the ability of women to mobilise nutrients from body stores seems to persist also between pregnancies, giving them, in effect, a better excretory system. Menstrual bleeding may have such an excretory function. In this light, at least a part of the blame for some human ailments falls on nutritionists whose thoughts still revolve around deficiency diseases when trying to determine the optimal daily intake of various food items. It might be time for them to forget rickets and concentrate on the harm done by excess intake! If the gender gap is, at least partly, due to the better ability of women to excrete some micronutrients, the lives of men could be prolonged by reductions in their intake. For instance, the dairy industry might attempt to produce de-calcified, or calcium-reduced milk. The food industry might abandon the assumption that breakfast foods are consumed exclusively by children and pregnant women, and cease to fortify them with iron.
Acknowledgement Conclusions Prosperity has brought great changes in our lives. Probably for the first time in the history of
My thanks are due to the referee of the paper, Dr. D. Hywel Davies, for constructive criticism and helpful suggestions for improvements.
119
References 1 Comfort 2 3 4
5
6
7
8
9 10 11
12
A. The Biology of Senescence. New York: Elsevier, 1979. Lopez AD. Sex differentials in mortality. WHO Chronicle 1984;38:217-224. Smith DWS. Is greater female longevity a general finding among animals? Biol Rev 1989;64:1-12. Phillips RL, Kuzma JW, Benson WL, Lotz T. Influence of selection versus lifestyle in risk of fatal cancer and cardiovascular disease among 7th Day Adventists. Am J Epidemiol 1980;112:296-314. Berkel J, De Waard F. Mortality pattern and life expectancy of 7th Day Adventists in the Netherlands. Int J Epidemiol 1985;12:455-459. Coronary Drug Project Research Group. Findings leading to the discontinuation of the 2.5 mg/day estrogen group. J Am Med Assoc 1973;226:652-657. Veterans Administration Co-operative Urological Research Group. Treatment and survival of patients with cancer of the prostate. Surg Gynecol Obstet 1967;124:1011-1018. Phillips GB. Evidence for hyperestrogenemia as a risk factor for myocardial infarction in men. Lancet 1976;ii:1418. Luria MH. Estrogen and coronary artery disease in men. Int J Cardiol 1989;25:159-166. Einfeldt H, Msller J. The Treatment of Cardiovascular Disease with Testosterone. Heidelberg, Springer, 1984. Goto Y. Tsushima M. Primary prevention of atherosclerotic vascular disease with ethylnandrol. Bull Eur Organ Control Circulat Dis 1977;2:94-100. Reichel R, Widhalm K. Lipids and lipoproteins during pregnancy. In: Widhalm K, Naito HK, eds. Recent Aspects of Diagnosis and Treatment of Lipoprotein Disorders. New York: Liss Inc.. 1988.
13 Seely S. Atherosclerosis or hardening of the arteries? Int J Cardiol 1989;22:5-12. 14 Hickler RB. Aortic and large artery stiffness: current methodology and clinical correlations. Clin Cardiol 1990;13: 3177322. 15 Laogun AA, Gosling RG. In vitro arterial compliance in man. Clin Phys Physiol Meas 1982;3:201-204. 16 Witteman JC. Kok FJ. Van Saase JLCM et al. Aortic calcification as a predictor of cardiovascular mortality. Lancet 1986;ii:1120-1122. 17 Seely S. Diet and coronary arterial disease: a statistical study. Int J Cardiol 1988;20:183-192. 18 Fison CA. Why do women and some other primates menstruate? Perspect Biol Med 1987:30:566-574. 19 Seely S. Possible reasons for the comparitively high resistance of women to heart disease. Am Heart J 1976:91:275280. 20 Deuster PA, Dolev A, Bemier Ll. Trostman UN. Magnesium and zinc status during the menstrual cycle. Am J Obstet Gynecol 1987;157:964-968. 21 Kolka MA, Stephenson LA. Control of sweating during the human of menstrual cycle. Eur J Appl Physiol 1989;58:890-895. 22 Kon SH. Biological autoxidation. Decontrolled iron: an ultimate carcinogen and toxicant. Med Hypoth 1978;4: 445-453. 23 Dormandy JA. Abnormal blood viscosity and intermittent claudication. Practical Cardiol 1983;8:102-122. 24 Liener IE, ed. Toxic Constituents of Plant Foodstuffs. New York: Academic Press, 1980. 25 Silvertone GA. Possible sources of food toxicants in: Seely S. Freed DLJ, Silvertone GA Rippere V. Diet-related Diseases: The Modern Epidemic. London. Croom Helm. 1985.
CARD10
Journal of Cardiology,
29 (1990) 113-119
113
01146
Editorial
The gender gap: why do women live longer than men? Stephen Department
of Cardiology,
Seely
University of Manchester,
U.K. The Royal Infirmary, Manchester,
V. K.
(Received 19 January 1990; revision accepted 27 June 1990)
Seely S. The gender
gap: why do women
live longer
than men? Int J Cardiol
1990;29:113-119.
In countries for which statistics are available, women outlive men by about 6 years. In developing countries the female advantage for survival - the gender gap - is probably less. It was also smaller in advanced countries in the past. For instance, it was only 2 years in the United States in 1920. The question is why women can derive a greater benefit than men from the changed living conditions associated with prosperity. In general terms, the suggested answer is that humanity is now in a transitional state between conditions when the greatest danger to life was starvation, and one in which that is superseded by surfeit and overnutrition. We are only beginning to realize that overabundance also has its hazards - the prosperity-related diseases. Women are better able to cope with overnutrition than men because they always had to mobilise stores of nutrients in the body for the purposes of procreation. The means used for mobilisation of such stores provides them with better facilities for the excretion of unwanted nutrients. Key words:
Lipid;
Arterial
disease;
Epidemiology
Introduction The gender gap is the difference between male and female expectation of life at birth, generally of the order of 6 years in favour of women in countries for which statistics are available. Table 1 shows data for 27 countries. The average in these countries is 6.4 years, ranging from 3.4 years in Cuba to 8.7 years in the U.S.S.R. Generally, the gender gap tends to increase with prosperity. In third-world countries it is probably low, as it was probably low in all countries in the past. Thus, in
Correspondence to: Dr. S. Seely, Dept. of Cardiology. The Royal Infirmary, Manchester, Ml3 9WL, U.K. 0167-5273/90/$03.50
1920, the gender gap was only 2 years in the United States, against its present value of 7.2 years. The correlation between the gender gap and prosperity, nonetheless, or between the gender gap and the average expectation of life for men and women, is irregular. Thus, the average expectation of life is currently highest in Japan at 79 years, where the gender gap, 6.2 years, is slightly below the average. In the U.S.S.R., the average expectation of life for both sexes is 69 years, with a gender gap of 8.7 years. Why do women live longer than men, and what is the reason for the gradual increase of the gender gap in the course of the present century? This paper takes a brief look at the problem and discusses some past ideas as well as possible lines of inquiry for future research.
0 1990 Else3ier Science Publishers B.V. (Biomedical Division)
114
Is there a general female advantage for survival? Some authors [1,2] believe that a female advantage for survival already exists in animals. Others [3] dispute this, and also point out that longevity in animals has little relevance to human lifespan. Wild animals do not reach their lifespan potential. Laboratory animals allowed to live under sheltered conditions do not die of the same diseases as we do. Thus, the chief cause of death in old laboratory rats is kidney failure - an infrequent cause of mortality in humans. Mortality statistics show that women are not less vulnerable than men to all diseases. In a few
TABLE
1
The gender gap in selected countries. Country
Date of statistics
Expectation of life Gender at birth, years gap (years) Male Female
Austria Belgium Denmark Finland France East Germany West Germany Hungary Italy The Netherl. Norway Portugal Spain Sweden Switzerland U.K. U.S.S.R. Canada Cuba Mexico U.S.A. Israel Japan Kuwait Sri Lanka Australia New Zealand
1987 1986 1986 1986 1986 1987 1987 1987 1985 1986 1986 1987 1984 1986 1987 1987 1986 1986 1986 1983 1986 1986 1987 1987 1983 1986 1986
71.6 70.9 71.9 70.6 71.8 69.9 72.2 65.7 72.2 73.1 72.9 70.6 73.2 74.0 74.0 72.4 65.1 73.1 72.7 65.8 71.4 73.4 75.9 72.5 66.6 73.0 71.1
78.2 77.7 77.8 78.9 80.0 76.0 78.9 73.9 78.8 79.8 79.9 77.5 79.8 80.2 81.0 78.3 73.8 79.9 76.1 71.6 78.6 77.0 82.1 75.8 71.6 79.6 77.5
6.6 6.8 5.9 8.3 8.2 6.1 6.7 8.2 6.6 6.7 7.0 6.9 6.6 6.2 7.0 5.9 8.7 6.8 3.4 5.8 7.2 3.6 6.2 3.3 4.8 6.6 6.4
Extracted from World Health Statistics Annual 1988, Geneva, 1988.
cases, female mortality is higher. Primary pulmonary hypertension and multiple sclerosis are two examples. The combined death rate from cancer of the breast, uterus and cervix is higher than from the corresponding causes, cancer of the prostate and testes, in men. Table 2 shows mortality rates for males and females in the age group from 65 to 74 from selected causes in a few countries. Generally, however, men die from most diseases at an earlier average age than do women. The most important disorders where women have a pronounced advantage for survival are arterial disease and some types of cancer, such as those of the digestive tract. Men are also more vulnerable to self-inflicted hazards, like smoking, and more die of accidents and violence. Male mortality from cancer of the lung, for instance, exceeds female mortality in the three countries shown in Table 2 by a factor ranging from 2.8 to 4.1. This is the presumable explanation of the low gender gap found in studies on 7th Day Adventists [4,5], who abstain from the consumption of alcohol and coffee, and are non-smokers. The gender gap probably springs from two roots. One is the apparent ability of women to derive a greater benefit from prosperity-related changes in living conditions. But, beside this, it seems unavoidable to assume some basic biological advantage for females in terms of survival. This advantage seems to apply to many diseases, so that the understanding of its causes needs the concerted efforts of specialists in many fields. The present paper is intended to discuss only the possible reasons for lower female mortality from arterial disease.
Possible causes of lower female mortality from arterial disease Sex hormones
When the problem began to be considered why men were more vulnerable than women to arterial disease, one of the early ideas was that oestrogens had a protective effect on the arteries. The assumption was thought to be supported by the rapid increase in female cardiovascular mortality
115 TABLE
2
Male and female mortality 198661987.
rates in the 65-74
Cause of mortality
age group
U.S., 1986 Male
Cancer of the breast, uterus and cervix Cancer of the prostate Cancer of the lung Cancer, total Coronary disease (acute myocardial infarction and other ischaemic heart disease) Cerebrovascular disease Multiple sclerosis Male/female mortality ratio Cancer, total Coronary Cerebrovascular Abstracted
from selected
England Female
1110.8 197.8 1.7
Health
Female
Statistics
Annuals,
England
Japan,
and Wales and Japan
146.4 644.6
514.1 150.5 2.0
1489.1 359.2 4.7
Female
43.6
154.8 752.9
23.6 229.7 1014.7
55.4 451.6
661 .o 274.2 6.2
192.5 369.3 4.1
96.5 234.4 6.5
1.71 2.25 1.31
in
1987
Male
170.9 109.1 496.4 1287.0
1.68 2.16 1.31
States,
and Wales. 1987
Male
138.9 107.3 407.5 1085.6
disease
from World
causes in the United
2.25 1.99 1.58
1989.
after the menopause, as if the decrease in the serum level of oestrogens at that time had attenuated some protective mechanism. This was the basis of the Coronary Drug Project [6], in which oestrogens were administered to male patients with coronary arterial disease in the hope that life would be prolonged. The result of this trial, as well as that of another trial initiated by the Veterans Administration [7], in which prostatic cancer patients were treated with oestrogens, demonstrated that these had an adverse effect on the arteries, increasing mortality from both coronary arterial and cerebrovascular disease in the treated group in comparison with controls. The ill-effects were so pronounced that, in the 196Os, medical opinion swung in the opposite direction, casting oestrogens in the role of pathogenic agents instead of remedies [g]. Recently, Luria [9] has surveyed the large volume of literature on the subject, concluding that the preoccupation with oestrogens has produced few useful results. Given large doses, oestrogens are harmful, probably acting as clotting agents, but under normal conditions they do not constitute an important risk factor of atherogenesis. Small-scale trials have also been conducted on the effect of testosterone on patients with coronary
arterial disease [lO,ll]. Apart from some unwanted androgenic effects, beneficial results were claimed for it, and work on modified steroids which would retain the useful features without the androgenic effects still continues. High-density lipoproteins The best-known differences between the male and female circulatory system which is likely to have a bearing on arterial disease is the greater concentration of high-density liproteins in the plasma of women: about 0.6 g/l in comparison with 0.45 g/l in male plasma. As these proteins carry cholesterol from peripheral tissues, and possibly from atheromatous plaques, to the liver for re-use or excretion, they probably play a significant part in the prevention or slowing down of the atherogenetic process. A large volume of literature is available on the subject. It is not intended to review it in detail. The presumed biological reason for the greater concentration of high-density lipoproteins in the plasma of women is the necessity of transferring nutrients from the maternal to the fetal circulation in pregnancy. Cholesterol is an essential component of cell membranes. The need for it in a
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continuously proliferating cell community is greater than in the adult body. There is, indeed, an increase of the concentration of lipoproteins both of high and low density - in the female circulation during pregnancy [ 121, indicating increased activity in both the synthesis of cholesterol and in its mobilisation from existing stores. The interaction of the maternal and fetal circulations is through the chorionic villi, the action of which is essentially similar to that of the intestinal villi of adults. They can exercise a degree of selection, concentrating some substances and rejecting others. While the need for a greater concentration of high-density lipoproteins arises mainly in pregnancy, women always maintain a higher store of them than men. This probably serves them well in the disposal of excess cholesterol at any time.
Calcium metabolism A similar, but less appreciated, difference could arise in connexion with the transfer of calcium (and possibly other minerals and trace elements) from the maternal to the fetal circulation in pregnancy, and from the mother to the offspring in lactation. This section is an attempt to explain why such transfer may represent a female advantage for survival. The diet of advanced countries includes an unnatural food - milk - not consumed by an adult animal except man. Nature designed milk for the needs of infants, whose growing skeleton needs more calcium in proportion to body weight than the adult body. Furthermore, various animals grow at a different rate. The human infant grows comparatively slowly; a calf, in contrast, reaches its adult size in 3 years, 5 or 6 times more quickly. Cow’s milk caters for their need, not for that of human adults. The body of a 70 kg adult male contains about 1.2 kg calcium, 99% of which is in the skeleton. The remaining 1% plays an essential part in many biological processes, like muscular contraction, which, however, do not consume calcium. Thus, in muscular contraction, calcium ions are released from the endoplasmic reticulum of muscles. They
trigger off contraction, after which they are actively withdrawn for further storage into the endoplasmic reticulum. Once the skeleton is at its maximum adult size, and the storage depots in body fluids, nerves, muscles, and so on are established, the need for calcium of the adult male body is nil, and that of the female body arises only in pregnancy or lactation. Zero consumption does not mean that the dietary intake could also be reduced to zero. Calcium is excreted by the kidneys, sweat glands and the liver. If calcium intake is too high, the kidneys have to do extra work by concentrating it in the urine. If it is too low, they have to do work to conserve it. The optimal intake is presumably that which minimizes the work of the kidneys, namely when the urine is isotonic with blood in respect of concentration of calcium ions. The human skeleton reaches its maximum size and weight at the age of about 35. It remains at this size for only about lo-12 years, after which time it begins to shrink. After the late forties, calcium released from the decreasing skeleton is added to a possibly already excessive dietary intake. At the same time, hard physical exertion is likely to become less frequent, reducing the amount of calcium lost in sweat. This may be the time when the excretory mechanism is unable to cope with its load and calcium excess becomes a hazard. The excess may be deposited in soft tissues, notably in arteries. The elasticity of the aorta is an essential requirement in the functioning of the circulatory system, because the energy stored in its distended elastic walls is needed for the maintenance of diastolic pressure. As it loses elasticity, an increasingly high systolic pressure is needed to maintain diastolic pressure at a given value [13]. The aorta and other large arteries gradually lose elasticity throughout life [14,15], in men at a higher rate than in premenopausal women.. After the menopause, the rate of stiffening of the female aorta increases and gradually becomes comparable with the male aorta. This process, which will be mentioned again in the next section, is multicausal, but the effects are additive. The calcification of the aorta is the last stage in the process and is a predictor of cardiovascular mortality [16].
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It may be pointed out that metabolism of calcium is a complex process, involving hormonal control and the presence of vitamin D for internal transport. Proteinaceous foods apparently facilitate the uptake of calcium from the intestines, others inhibit it. The fact remains that, in old age, several of these factors become confluent to result in the calcification of soft tissues. In advanced countries, up to 80% of the dietary intake of calcium may come from milk and dairy products. Apart from the already outlined physiological causes, the strong statistical correlation between consumption of milk and death froin coronary arterial disease [17] draws attention to the possibility that the daily intake of calcium, regarded normal by nutritionists at 600-1000 mg per day is, in fact, excessive. There are no signs of calcium deficiency in countries where the calcium intake is around 400 mg/day. The average woman in advanced countries gives birth to two children. During pregnancy and, when it applies, during the subsequent period of lactation, the usual process of calcium accumulation may be at a standstill, or may even be reversed, by calcium being withdrawn from the skeleton. In addition, as will be discussed later, menstruation may play a part in the regulation of micronutrients, like calcium, representing a factor in female advantage for survival. Iron metabolism
and haematocrit
The adult human body contains 4-5 g of iron, about 70% of which is in haemoglobin. The rest is protein-bound, mainly in large ferritin molecules, possibly as a reserve for haemoglobin. The turnover of iron in the body is minimal. When red blood cells die, their content of haemoglobin is transferred to nascent blood cells. Urine contains only a minute amount of iron. There is no true excretory pathway for iron: the main regulatory mechanism is the control of its absorption from the intestines. The body possesses various mechanisms for the excretion of substances which present difficulties for the normal excretory channel. Arsenic, for instance, is incorporated into hairs and nails, and is eliminated as they grow out of the body. In
other cases some cells scavenge pathogenic matter and work their way out of the body, carrying the pathogens with them. When the need arises, this method is used in the case of iron. Cells of the intestinal mucosa, laden with ferritin, are sloughed into the intestines. Menstruation may represent a similar pathway. Women in their reproductive period may absorb more iron and other micronutrients in the anticipation of pregnancy than their normal needs. If pregnancy does not follow, they excrete this material in menstrual bleeding. Medical science has paid little attention to the possible function of menstruation, even if some authors do take up the matter [18]. I suggested some years ago [19] that its function was excretory. Apart from iron, menstrual cycling may play a part in the regulation of various minerals, like magnesium and zinc [20]. Beside bleeding, menstrual cycling appears to involve bouts of sweating [21], with a possible effect on calcium excretion. Whatever the exact mechanism may be, it appears that women age more slowly than men while menstrual periods last, but lose this advantage after the menopause. The control of the uptake of iron from the intestine is faulty in some individuals. From such cases the toxic and carcinogenic effect of excess iron on the liver, pancreas and other organs is well known. Kon [22], however, suggests that the minute amounts of iron in body fluids play an important part in the aging process even in normal individuals. Iron finds its way into all tissues and acts as an oxidising agent, causing the oxidative cross-linking of protein fibres. This is a recognised cause of the loss of elasticity and gradually increasing rigidity in soft tissues. The possibility, therefore, exists that a regular removal of surplus iron in menstrual bleeding has a beneficial effect on the aging process, and represents another instance of female survival advantage. Another difference between the two sexes is the lower haematocrit of women. The normal volume of packed red cells is about 0.45 l/l in men, 0.41 l/l in women. The haematocrit is an important determinant of the viscosity and flow properties of blood, sometimes of critical significance in narrowed arteries.
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No satisfactory explanation exists for the higher haematocrit of men. Dormandy [23] suggest that the human haematocrit is higher than its optimal value. At least on some occasions the oxygencarrying capacity of blood can be improved by haemodilution, the modern equivalent of the time-honoured practice of bloodletting, because the gain from increased blood flow, resulting from lower viscosity, is greater than the loss from a lower proportion of haemoglobin in the blood. According to Dormandy [23], the present level of haematocrit might have been optimal in the past, when the risk of blood loss from injuries was greater, but the evolutionary process has so far failed to respond to changing environmental conditions. The problem of the higher male haematocrit is an intriguing one. Beside the possibility suggested by Dormandy [23] that it might be useful in the case of injuries, its conceivable function could be higher endurance. It is interesting to note, in this connexion, the great variety of haemoglobin-like iron proteins in invertebrates, with atomic weights ranging from 17,000 to 1,275,OOO. The largest of these erythrocruorins are thought to serve as stores for oxygen, presumably for emergencies, not transport. The aim of having an oxygen reserve in the body seems to have deep roots in evolutionary history, and the higher than optimal haematocrit of men may be another example of this trend. Be this as it may, the high male haemotocrit seems to have a negative value, for survival under present conditions. It might be mentioned that the human circulatory system is the target organ of a legion of plant toxins [24,25]. For instance haemagglutinins which can cause aggregation of red cells and greatly increase blood viscosity, are produced by a host of plants: beans, peas, lentils, cereals, potatoes, peanuts, bananas. All these hazards suggest that a haematocrit erring on the low side is now more conducive to longevity than one on the high side.
terrestrial life, the danger of starvation and malnutrition has been removed from at least some human communities, and was superseded by that of overnutrition. The result of the excess intake of macronutrients, coupled with the natural thrift of the body always prepared for possible periods of starvation, is obvious enough in overweight individuals. The less appreciated hazard is that when the same thing happens with micronutrients, like calcium and iron, there are no immediate signs of unwanted accumulations. Nevertheless, such minerals in excess may play a major part in the pathogenesis of some prosperity-related disorders, like arterial disease. The female advantage for survival may arise in prosperous countries by the innate ability of the female body to mobilise and transport nutrients for the benefit of the fetus in pregnancy. Apart from the quantity of nutrients transferred to the fetus, the ability of women to mobilise nutrients from body stores seems to persist also between pregnancies, giving them, in effect, a better excretory system. Menstrual bleeding may have such an excretory function. In this light, at least a part of the blame for some human ailments falls on nutritionists whose thoughts still revolve around deficiency diseases when trying to determine the optimal daily intake of various food items. It might be time for them to forget rickets and concentrate on the harm done by excess intake! If the gender gap is, at least partly, due to the better ability of women to excrete some micronutrients, the lives of men could be prolonged by reductions in their intake. For instance, the dairy industry might attempt to produce de-calcified, or calcium-reduced milk. The food industry might abandon the assumption that breakfast foods are consumed exclusively by children and pregnant women, and cease to fortify them with iron.
Acknowledgement Conclusions Prosperity has brought great changes in our lives. Probably for the first time in the history of
My thanks are due to the referee of the paper, Dr. D. Hywel Davies, for constructive criticism and helpful suggestions for improvements.
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