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PAPERS: D A Lawlor, S Ebrahim, and G Davey Smith Sex matters: secular and geographical trends in sex differences in coronary heart disease mortality BMJ 2001; 323: 541-545 [Abstract] [Full text]

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Sex differences in coronary heart disease mortality is really complex

Sergio Stagnaro   (10 September 2001)

Sex matters and gender matters

Judith Lorber   (11 September 2001)

Oestrogen may contribute to variation in sex differences in coronary heart disease mortality

Tessa M Pollard, Colin Fischbacher, Nigel Unwin   (22 September 2001)

Sex may well matter, but is it old-fashioned to say so?

Cecily Kelleher   (6 December 2001)

Sex differences in coronary heart disease mortality is really complex 10 September 2001
Sergio Stagnaro, Specialist in Blood, Gastrointestinal and Metabolic Diseases Riva Trigoso (Genoa) Italy Send response to journal: Re: Sex differences in coronary heart disease mortality is really complex	Sir, In my opinion, based on 44 years of clinical experience, sex differences in causing mortality from coronary heart disease recognize more complex explanation than those stated in the otherwise interesting paper. Certainly, mortality from coronary heart disease is greater in men than women in most industrialised countries, but underlining almost exclusively the differences on fat intake, overlooking other risk factors such as sympathetic hypertonus as well as the modified reaction of coronary vessels (and other arteries) to insulinaemia under such situation, it seems to me that Authors explain the above-mentioned problem too simply for the truth to be told. In addition, in order to understand better the pathophysiological mechanisms of the well kown differences, mentioned above, we have to consider accurately the different micro- and macro-vascular responses to insulin (and GH) in healthy and in stressed people, as well as endothelial dysfunction that may be congenital or even exist in apparently healthy people (1). The microcirculation in healthy, non-distressed people ameliorates clearly when evaluated clinically (2) during jatrogenetically increased blood levels of both hormones. On the contrary, microcirculation appears compromised in patients with endothelial dysfunction, regardless of its nature, including nervous-stress. I think that there is a fundamental congenital pathological condition, made worst by sympathetic hypertonus, that affects endothelial cells selectively in microvessels and, later, in macrovessels, such as the coronary artery (2), because of pathophysiological events. I termed this congenital mitochondrial disorder "Congenital Acidosic Enzyme- Metabolic Histangiopathy (3,4). Stagnaro Sergio MD., Member NYAS and AAAS 1)Stagnaro-Neri M., Stagnaro S., Semeiotica Biofisica: valutazione clinica del picco precoce della secrezione insulinica di base e dopo stimolazione tiroidea, surrenalica, con glucagone endogeno e dopo attivazione del sistema renina-angiotesina circolante e tessutale – Acta Med. Medit. 13, 99 1997 2)Stagnaro-Neri M., Stagnaro S., Deterministic Chaos, Preconditioning and Myocardial Oxygenation evaluated clinically with the aid of Biophysical Semeiotics in the Diagnosis of ischaemic Heart Disease even silent. Acta Med. Medit. 13, 109 1997. 3)Stagnaro S., Istangiopatia Congenita Acidosica Enzimo-Metabolica. X Congr. Naz. Soc. It. di Microangiologia e Microcircolazione. Atti, 61. 6-7 Novembre, Siena 1981. 4)Stagnaro S., Istangiopatia Congenita Acidosica Enzimo-Metabolica. Gazz Med. It. – Asch. Sci, Med. 144, 423 1985
Sex matters and gender matters 11 September 2001
Judith Lorber, Professor Emerita Graduate School, City University of New York, NYC Send response to journal: Re: Sex matters and gender matters	Both the title of the paper by Lawlor et al.(BMJ Sept 8) -- "Sex matters: secular and geographical trends in sex differences in coronary heart disease mortality" -- and your editorial comment have completely confused sex and gender: "A group from Bristol grabs attention by arguing that the fact that men have much higher rates of heart disease than women may be nothing to do with gender (p 541)." Lawlor et al.'s findings have little to do with sex (oestrogen was not the protective factor) and everything to do with gender -- men's rates of CHD rose precipitously in the years when red meat was scarce, and they had the privilege of eating more of it: "Historical reports covering the United Kingdom and other European countries have shown that food consumption was differentiated within families along the lines of age and sex at this time, with men in general being given more meat." As with many other such findings about sex differences, the crucial factor tends to be gendered patterns of behavior.
Oestrogen may contribute to variation in sex differences in coronary heart disease mortality 22 September 2001
Tessa M Pollard, *Lecturer, **Lecturer, ***Senior Lecturer *University of Durham, ** and *** University of Newcastle, Colin Fischbacher, Nigel Unwin Send response to journal: Re: Oestrogen may contribute to variation in sex differences in coronary heart disease mortality	Lawlor et al1 have outlined geographical and historical variation in sex differences in coronary heart disease (CHD) mortality, noting that a higher intake of energy from fat was significantly associated with a higher male:female CHD mortality ratio. They suggest that these findings cannot be explained by variation in oestrogen levels, because oestrogen may not, as widely believed, protect against CHD and because, in any case, oestrogen levels are not variable across populations or history. We suggest that the possibility that oestrogen may play a role in explaining their findings cannot be dismissed on either of these counts. There is a large body of evidence indicating that oestrogen protects women against CHD, partly by causing less atherogenic serum lipid profiles, and several biochemical pathways by which oestrogen could exert such an effect have been identified2. Further, studies have shown that ovarian function and oestrogen levels differ markedly in women in different populations. Jasienska and Thune3 have recently outlined some of the evidence for variation in ovarian function and have argued that it is associated with population variation in breast cancer rates. Similarly, Bernstein and Ross4 cite several studies showing low oestrogen levels in premenopausal and postmenopausal women in populations with low breast cancer rates, including rural China and rural Japan. In industrialised countries there has been a trend towards earlier menarche over the last 100 years5, suggesting that level of ovarian function has been increasing4, and demonstrating that oestrogen levels are likely to vary over time as well as geographically. A number of studies have demonstrated a positive association between nutritional status and ovarian function3,5. Some studies have shown that higher fat intake is associated with higher endogenous oestrogen levels4. Thus it is possible that the relative protection against CHD afforded to women by oestrogen is greater in countries with higher fat intake, leading to a bigger gap between male and female CHD mortality in such countries. Correspondingly, it is also possible that the observed positive association between changes in fat consumption and changes in the male:female CHD mortality ratio in England and Wales could be partially explained by changes in oestrogen levels, protecting women and increasing the male:female mortality ratio when fat intakes increased. In conclusion, a balanced view of the evidence currently available suggests that variation in oestrogen levels, between populations and over time, must be considered as at least part of the explanation of Lawlor et al's findings. 1. Lawlor DA, Ebrahim S, Davey Smith G. Sex matters: secular and geographical trends in sex differences in coronary heart disease mortality. BMJ 2001;323:541-5. 2. Mendelsohn ME and Karas RH. The protective effects of estrogen on the cardiovascular system. New England Journal of Medicine 1999;340:1801- 11. 3. Jasienska G, Thune I. Lifestyle, hormones, and risk of breast cancer. BMJ 2001;322: 586-7. 4. Bernstein L, Ross RK Endogenous hormones and breast cancer risk. Epidemiologic reviews 1993;15:48-65. 5. Wood JW. Dynamics of human reproduction. New York: Aldine de Gruyter, 1994.
Sex may well matter, but is it old-fashioned to say so? 6 December 2001
Cecily Kelleher, Professor of Health Promotion Clinical Sciences Institute, National University of Ireland, Galway, Republic of Ireland. Send response to journal: Re: Sex may well matter, but is it old-fashioned to say so?	The authors assert that the oestrogen-related effect on CHD is not consistent with the period effect they demonstrate. Yet this was in all likelihood an epidemic of coronary thrombosis, not just ischemic heart disease, which makes crucial the inter-relationship between the coagulation system and the processes that lead to atheroma. As Meade et al suggested (I), in men with pre-existing atheroma the addition of estrogen may be deleterious, since it leads to some net enhanced coagulability against a background of established risk, a plausible explanation for the failure of oestrogen trials previously. In women before menopause, oestrogen has beneficial effects on the HDL/LDL profile but also on the coagulation system, a combined mechanism for explaining the gradual narrowing of risk between men and women over time. An interaction with diet, a very well established partial explanation for coronary heart disease (2), would be delayed considerably in women and might not occur at all with net shifts in risk factor predisposition. A similar rank order of risk of CHD for men and women between countries is consistent with a shared environmental exposure acting differentially for men and women. The use of age standardisation demonstrates the period effect clearly, but could obscure any more modest cohort or time-course trend, which age-specific rates, not reported here, might clarify, rather than presentation only of ratios. A case in point is the age cross-over of breast cancer incidence in black and white women, masked by the use of age standardisation for comparison (3). Are the authors saying that there was no rise in risk of heart disease among post menopausal women at any point in this epidemic, congruent with the rates in younger men? References: 1. Meade TW, Dyer S, Howarth DJ, Imeson JD, Stirling Y. Antithrombin-III and procoagulant activity-sex differences and effects of the menopause. British Journal of Haematology 1990; 74: 77-81. 2. Hu FB, Stampfer MJ, Manson JE et al. Trends in the incidence of coronary heart disease and changes in diet and lifestyle in women. NEJM 2000: 343: 530-537. 3. Pathak DR, Whittemore AS. Combined effects of body size, parity, and menstrual events on breast cancer incidence in seven countries. Am J Epidemiol 1992; 135: 153-68. Competing interests: none