Programa Cronicat, Institute of Health Studies, Barcelona, Spain.
SirIn the review of Epidemiology in the IJE in February the increasing obesity in the United States over the 1990s across, apparently, all subgroups of the population1 was mentioned. What is even more perplexing is that all this is happening while there is an inexorable decline in cardiovascular disease in that country. Hypotheses abound to explain the decline in cardiovascular disease observed in many countries. Ingster and Feinleib have made2 a coherent argument for salicylates in the food chain contributing to the decline in cardiovascular disease in the USA. The authors admit that there are many gaps in this syllogism which must be addresssed. One such gap which needs to be filled is provided by the meta-analysis of 61 studies which supports3 the case for a significant decline in human sperm densities in the USA and Europe. There are considerable data suggesting that this may be caused by other substances entering the food chain, i.e. pollutants, e.g. xenoestrogens (environmental hormones), pollutants with oestrogen mimicking effects (phenolics such as bisphenol A, phthalates, polychlorinated biphenyls, and diverse organo-chlorine pesticides) and naturally occurring dietary oestrogens, including flavonoids and other phytoestrogens.4 How might oestrogens protect against cardiovascular disease? Among other actions, it has been shown that they inhibit vascular smooth muscle proliferation which is a central feature of atherosclerosis.5,6
A fairly recent report7 from the Worldwide Fund for Nature catalogues the presence of more than 350 chemicals from substances such as perfume, sun-tan lotion and pesticides, in human breast milk samples, including 87 dioxin and dioxin-like compounds. After the Seveso incident in 1976, in which large amounts of tetrachlorodibenzo-p-dioxin were liberated, a preponderance of female births was noted over the half life of the toxin. The authors felt this observation might support the hypothesis that dioxin modified hormonal balance8 but offered other explanations as well. A fair proportion of these have oestrogen mimicking effects. Even more contaminants are likely to be present because other toxic chemicals found in human body fat can potentially transfer to the newborn infant during breastfeeding. Indeed, exposure to them in utero and through breastfeeding might be acting in tandem with those postulated in the fetal/infant origins of adult cardiovascular disease hypothesis.9
Alcoholic beverages, particularly red wine, are a source of exogenous oestrogenic substances. Indeed alcoholic males are well known to exhibit signs of feminization, but not until cirrhosis ensues.10 If this is proven, increases in moderate alcohol consumption, especially in the form of wine, could explain the decline in heart disease in both sexes: men becoming more like women and women becoming even more like women in terms of arterial disease. In addition, Ingster and Feinleib suggest2 that their hypothesis might also contribute to an understanding of why the decline in mortality has continued despite a steady increase in the prevalance of obesity in the USA. This increase has been particularly marked between NHANES II and NHANES III.11 It is well known that adipose tissue produces oestrogen12 and this might also be contributing to the decline. Indeed, it has been observed12 that Morbidly obese patients possess an unlimited reservoir for peripheral estrogen synthesis.
The decline in cardiovascular disease and increase in obesity has also been accompanied by a fall in blood pressure13 and total cholesterol,14 while evidence for high density lipoprotein (HDL) cholesterol change is more controversial.15,16 This pattern of risk factor change has also been observed in other countries.17 There is emerging evidence that some genetic polymorphisms which have been shown to add to cardiovascular risk seem to depend upon increased body weight for their expressions.18 Although the overall level of alcohol consumption in the USA has remained fairly constant over the period of the decline in cardiovascular disease, the per capita consumption of wine is reported,19 albeit by the wine industry, to have doubled. Thus, the situation is highly perplexing and the hypothesis for an oestrogen-driven decline deserves exploration.
Lastly, perhaps the title needs some explanation: oestrogens induce oestrus which is derived from the Greek for gadfly.20
References
1
Davey-Smith G, Ebrahim S. EpidemiologyIs it time to call it a day? Int J Epidemiol 2001;30:111.
2 Ingster LM, Feinleib M. Could salicylates in food have contributed to the decline in cardiovascular disease mortality? A new hypothesis. Am J Public Health 1997;87:155457.[Abstract]
3 Swan SH, Elkin EP, Fenster L. Have sperm densities declined? A reanalysis of global trend data. Environ Health Perspect 1997;105: 122832.[ISI][Medline]
4 Safe SH, Gaido K. Phytoestrogens and anthropogenic estrogenic compounds. Environmental Toxicology & Chemistry 1998;17:11926.
5
Morey AK, Pedram A, Razandi M et al. Estrogen and progesterone inhibit vascular smooth muscle proliferation. Endocrinology 1997;138: 333039.
6 Kikuchi N, Urabe M, Iwasa K et al. Atheroprotective effect of estriol and estrone sulfate on human vascular smooth muscle cells. J Steroid Biochem Mol Biol 2000;72:7178.[ISI][Medline]
7 Executive summary. Chemical trespass: A toxic legacy. A Worldwide Fund for Nature-UK report, June 1999.
8 Mocarelli P, Brambilla P, Gerthoux PM, Patterson DG, Needham LL. Change in sex ratio with exposure to dioxin. (Letter) Lancet 1996; 348:409.[ISI][Medline]
9 Barker DJP. Foetal and infant origins of adult disease. London: British Medical Association, 1992.
10 Gavaler JS, Rosenblum ER, Deal SR, Bowie BT. The phytoestrogen congeners of alcoholic beverages: current status. Proc Soc Exp Biol Med 1995;208:98102.[Abstract]
11 Flegal KM, Carroll MD, Kuczmarski RJ, Johnson CL. Overweight and obesity in the United States: prevalence and trends, 19601994. Int J Obesity & Rel Met Dis 1998;22:3947.
12 Hansen LM, Batzer FR, Corson SL, Bello S. Obesity and GnRH action. Report of a case with contribution by peripherally derived estrogens. J Reproductive Med 1997;42:24750.
13
Burt VL, Culter JA, Higgins M et al. Trends in the prevalence, awareness, treatment, and control of hypertension in the adult US population. Data from the health examination surveys, 1960 to 1991. Hypertension 1995;26:6069.
14 Sempos Ct, Cleeman JI, Carroll MD et al. Prevalence of high blood cholesterol among US adults. An update based on guidelines from the second report of the National Cholesterol Education Program Adult Treatment Panel. JAMA 1993;269:300914.[Abstract]
15 Derby CA, Feldman HA, Bausserman LL, Parker DR, Gans KM, Carleton RA. HDL cholesterol: trends in two southeastern New England communities, 19811993. Ann Epidemiol 1998;8:8491.[ISI][Medline]
16 Johnson CL, Rifkind B, Sempos C et al. Declining serum cholesterol levels among US adults. The National Health and Examination Surveys. JAMA 1993;269:300208.[Abstract]
17 Kuulasmaa K, Tunstall-Pedoe H, Dobson A et al. Estimation of contribution of changes in classic risk factors to trends in coronary event rates across the WHO MONICA Project populations. Lancet 2000;355:67587.[ISI][Medline]
18
Gerdes C, Fisher RM, Nicaud V et al. Lipoprotein lipase variants D9N and N291S are associated with increased plasma triglyceride and lower high-density lipoprotein cholesterol concentrations: studies in the fasting and postprandial states: the European Atherosclerosis Research Studies. Circulation 1997;96:73340.
19 http://www.wineinstitute.org/communications/statistics/consumption 193495.html (Edited March 30, 1998).
20 Dorland's Illustrated Medical Dictionary (24th edn.) Philadelphia and London: WB Saunders Co, 1965, p.1036.