Useless info overdose.....
Do women really have lower rates of heart disease? If so, what are the mechanisms and is HRT any good?
Introduction
Cardiovascular diseases are by far, the largest group of diseases killing women in the United Kingdom, accounting for 38% of all female deaths in 2001. (Refer to figure 1) Among the various forms of cardiovascular disease, heart disease and stroke are the most common circulatory problems, with heart disease taking the lead, claiming one in every 6 women and one in every 4 men. (The British Heart Foundation 2003)
Looking at the figures, it can be seen that in the UK, women are less likely to suffer from heart disease than men. When the heart disease rates between the sexes were compared between over 50 countries in a review done over 12 years ago,(Kalin MF & Zumoff B 1990) the trend of women having lower rates of heart disease holds true among all the different sample populations. Although the absolute rates of heart disease were different in all the countries, a relative consistent ratio of male to female suffers was obtained through different sample populations in different countries. (Figure 2)
Why women are at less risk
The universal lower rates of heart disease in women suggests that there must be some form of protection against heart disease in women when compared to the men. The difference in absolute heart disease rates among different populations suggests strongly that these protective mechanisms are not independent of social and environmental factors. Another trend in heart disease in women is that although their heart disease rates do not catch up to that of the men, there is a significant increase in the rates after menopause. This suggests that the ‘protection’ that women enjoy from heart disease may have something to do with the presence of oestrogen during their fertile years.
Several mechanisms have been proposed so far in an attempt to explain the gender differences in cardiovascular disease rated between men and women.
1) Women and men have different sex-specific oestrogen receptors in their coronary arteries. Studies have shown that in vivo, oestrogen reverses the vasoconstriction caused by acetylcholine in postmenopausal women but not in men. Coronary blood flow was also significantly improved by oestrogen in women but not in men in this study. (Collins P et al. 1995) This suggests that oestrogen presence is contributing to the lower rates of heart disease in pre-menopausal women, and there are also different receptors or receptor responses involved in the cardio protective mechanisms of men and women. The difference in response in oestrogen may explain why oestrogen is only seen to be more cardio protective in women than men. As this study was done on men and post-menopausal women with proven cardiovascular disease, it avoids selection bias on healthy individuals that were unlikely to be suffering from cardiovascular conditions in the first place.
2) Other than the presence of cardio protective oestrogen produced by pre menopausal women, a study done on the lipid profiles of women worldwide also suggested that the presence of the oestrogen was not the only reason why they have lower heart disease rate than men. It was found that women reacted differently from men when they had ingested a high fat diet. When men had a high fat diet, their HDL and LDL levels remained the same, but when women has a high saturated and monounsaturated fat diet, their HDL levels are raised with the presence of the fats in the diet. This was attributed to a concurrent increase in female sex hormones levels with the high fat diet. (Kesteloot H & Sasaki S 1993) The rise of the HDL levels may play a significant beneficial role through the removal of cholesterol esters from the circulation in the women.
3) It was also observed that after menopause, the HDL levels of women does not decrease but it remains higher than the average levels of HDL in men. What changes with the onset of menopause is the increase of LDL levels. (Davis CE et al. 2002)It has been known for some time that the absolute LDL and HDL levels are poorer markers of heart disease risk when compared to the ratio of the lipids. The increase of LDL levels would then lower the HDL to LDL ratio, which is consistent with the observation of increased cardiovascular disease rates in women after menopause. This may be mediated by the decrease of LDL receptors involved in LDL uptake into the cells. Oestrogen has been demonstrated to induce the expression of LDL receptors in liver hepatocytes in vivo. This may be an important mechanism for the clearance of LDL from the circulation for pre-menopausal women.(Parini P, Angelin B, & Rudling M 1997)
4) Smoking is know to have a negative effect in HDL and fibrinogen levels.(Cullen P, Schulte H, & Assmann G 1998) Decreased HDL levels and increased fibrinogen levels are all independent risk factors for cardiovascular disease. The ‘protection’ that women has been observed to be enjoying may have been over reported due to confounding in the studies. Women in the past used to have lower smoking rates than men until recent years when the trend has changed for the younger population. Prospective studies in the future may demonstrate a lower level of protection in women against cardiovascular disease as their smoking levels increases above the smoking rates of the men.
5) Another mechanism that may work towards the advantage that women enjoy is in their body fat distribution. Women and men have different body fat distribution. Women are more prone to trunkal obesity and men are more prone to central obesity. When adjusted for BMI, it has been demonstrated that individuals with central obesity are more susceptible to cardiovascular disease than those with trunkal obesity. The trunkal distribution of fat in women may also serve to protect them from heart disease.(Larsson B et al. 1992) The difference in fat deposits may possibly be the result of natural selection. The traditional view of men as the hunters, would require a faster mobilisation of energy reserves in the pursuit of prey and visceral fat serve as the best choice of storage as it can be rapidly mobilised and metabolised directly as it passes the liver. Women on the other hand were selected for hip and buttock deposition as these reserves hare much harder to mobilise unless there is pregnancy or lactation, providing energy reserves when they are needed most. Some circumstantial evidence can be seen from a study that shows men are much more efficient in mobilising visceral fat by b-adrenergic lypolysis than pre and post-menopausal women(Rebuffe-Scrive M et al. 1989).
6) Homocystine levels have also been identified as an independent risk factor for cardiovascular disease. Higher rates of homocystine were closely linked to increased rates of heart disease through arterial endothelial dysfunction(Woo KS et al. 1997). Pre-menopausal women are generally found to have lower rates of homocystine(Verhoef P et al. 1999). A studt of male to female and female to male transsexuals demonstrated that homocystine levels were directly linked to the presence of oestrogen in both genetically male and female individuals(Giltay EJ et al. 1998).
7) Highly stressed out individuals and type A personalities are much more prone to heart disease. The stress associated with these social situations modulates the hypothalamus-pituitary-adrenal axis to increase levels of cortisol. Cortisol’s anti-insulin effects are thought to aid in the process of atherosclerosis through raising the blood glucose, pressure and triglyceride levels. Women in general are less aggressive than men and have better social network support to deal with the pressure of life(Porter M, Alder B, & Abraham C 1999). As such, they are more likely to have lower stress levels over the longer term and thus less likely to suffer from cardiovascular diseases mediated through this pathway.
The value of hormone replacement therapy
The earlier studies done in the 1980’s had produced conflicting results on the value of oestrogen replacement. There was still no firm conclusion on the effect of hormone replacement therapy (HRT) as a way of reducing cardiovascular diseases in post-menopausal women.
In the early 1990’s the long-term studies performed on the benefits of HRT started to pour in and there was a lot of support generated for the use of HRT as a means of preventing cardiovascular disease. To quote the conclusion of one of the earlier study, “Estrogen use was found to have a significant, independent effect on survival in women” (Sullivan JM et al. 1990)
The 10-year nurses study strongly supported the use of HRT as a means of reducing the rate and mortality of cardiovascular diseases. (Stampfer MJ et al. 1991) Reviews were soon haling the benefits of HRT use as a means of preventing cardiovascular disease and prolonging life in women.(Grady D et al. 1992) Other studies also strongly supported the use of HRT to lower mortality rates in post-menopausal women after coronary artery bypass surgery. (Sullivan JM et al. 1997)
Further randomised double blind trials were also carried out to verify support for the use of HRT as a means of preventing cardiovascular disease in post-menopausal women. Results from these trials started to pour in starting in 1998 and surprisingly, they were found to contradict the results of the former trials. Some of the more significant trials and their results reported are outlined below
HERS – Heart and Estrogen Replacement Study.
This was a randomised double blind trial involving 2763 women. Equine conjugated oestrogen was given to the subjects together with progesterone. Results obtained showed an increase in HDL levels and a decrease in LDL levels for the treated group when compared to the placebo group. However, there was an increased in the incidence of thrombolytic events and gall bladder problems in the treatment group with no net benefits in all other end points measured. (Hulley S et al. 1998)
ERA – Estrogen Replacement and Atherosclerosis trial
This was another double blind trial aimed at looking at the effect of HRT on atherosclerosis. 309 women with atherosclerosis was recruited and the study was randomised into 3 arms. Oestrogen only, oestrogen and progesterone, and placebo only. The study produced similar results to the HERS trial with an improved lipid profile but no significant benefit of either treatment group over the observed over the placebo group. (Herrington DM et al. 2000) In 2002, the oestrogen and progesterone arm of the study was halted after only 5.2 years out of a planned 8.5 years. This was because of excessive risk observed in the arm where the subjects had increased rates of cardiovascular events and invasive events.(Writing Group for the Women's Health Initiative Investigators 2002)
PHOREA – Postmenopausal HOrmone REplacement against Atherosclerosis
This trial was designed to measure the effect of HRT on slowing down the rate of atherosclerosis. 321 women were recruited for this trial and the thickness of their intima media in their carotid arteries were measured over 48 weeks. As with the other trials, there was significant improvement in the lipid, cholesterol and fibrinogen profiles of the treated group but there was no observable benefit in decreasing the rate of atherosclerosis. (Angerer P et al. 2001)
WEST – Women’s Estrogen for Stroke Trial
This trial was designed to measure the effectiveness of HRT as a means of reducing mortality and morbidity in patients with stroke. 625 women were recruited within 90 days of them suffering either a transient Ischaemic attack or a non-disabling stroke. The overall mortality rate was slightly higher in the treated group than in the untreated group. Vaginal bleeding and endometrial hyperplasia was also found to be more common in the treated group. The rates of non-fatal strokes were the same in both the treated and placebo group, but what was most alarming was that the treated group suffered from strokes that were associated with slightly worse neurological and functional deficits. (Viscoli CM et al. 2001)
Discussion
Due to all the negative reports on the use of HRT as a means of protection against heart disease, the American Heart Association had released a statement recommending against using HRT as a form of treatment or prevention against cardiovascular disease.(Mosca L et al. 2001) The stand that the American Heart Association took is hardly surprising in view of the current information available.
It is however interesting to note that all these studies have one common result, that is that there is always an improvement in the lipid profiles of the treated group, and where fibrinogen and homocystine levels were measured, these too shows marked improvement.
Another very interesting observation among the larger trials is that the adverse effects always gradually taper off. The overall lack of benefits in these studies have been suggested to be the result of confounding, where the gradual gain of benefits by the treated group was nullified by the mortality and morbidity obtained in the first year of study. If the mortality and morbidity of the first year was separated into the 4 quarters, it was also observed where the rate of incidence of negative events were highest in the first quarter and gradually decreases from quarter to quarter. It may be highly possible that these individuals form different genetic pool where they are actually slightly susceptible to the negative effects of HRT. When these individuals were take out of the studies as a result of death or reaching a negative end point, they are taken out of the general pool. The individuals left in the general pool would then consist of those who were benefiting from HRT. This will explain why there is always an apparent increase in risk of the first years followed by benefits in the long run.
Another possible problem in these studies were that most of them were using conjugated equine oestrogen and not recombinant human oestrogen. Although equine oestrogen may have been tried and tested for use as HRT, there will be innate differences between human and equine forms of oestrogen. These minor differences may have failed to activate or over activated one or more receptors of the human oestrogen in the ‘susceptible gene pool’ as mentioned above. These slight differences may actually be responsible for the negative effects seen in HRT.
Another possible cause of the differences in benefits recorded between individuals may be due to the pharmaceutical dosage given to them. Individuals will have their own optimal levels circulation hormones. In the trials, the hormones were given in a one size fits all manner. These generalised dosages of oestrogen may have been in the therapeutic ranges for some individuals, under the therapeutic ranges in other individuals and in some, they may actually be in the toxic ranges. It we look at all the different side effects of menopause seen by different women, where some suffer terrible hot flushes for years, and other passing through the phase relatively mildly, this dosage theory may not sound that far fetched after all.
As more and more studies are reported, they only serve to make the general picture of HRT more complicated. We are unlikely to elucidate the mechanisms of HRT in the promotion or prevention of cardiovascular disease anytime in the near future. There are too many possible mechanisms involved and large randomised studies are expensive and time consuming to conduct clinically. An ideal future study would include the subjects from their pre-menopausal yeas and a follow up to their deaths, similar to Professor Richard Doll’s ground breaking cohort study on smoking (Doll R et al. 1994), but in this instance, a general random sample of the population would have to be followed up. Using only healthcare professionals will confound the study through selection bias. Following up a random population sample would be a logistical nightmare, if not almost impossible for such an extended period of time.
We are all aware that the ‘protection’ conferred to women in terms of cardiovascular disease is multi factorial. Much effort and resources have been placed into this field of research and we have more knowledge than we ever had before, but we are still nowhere nearer to solving this great HRT debate since the first studies in the 1980’s. Evolution may yet hold an explanation behind this phenomenon that had baffled countless generations of doctors.
Evolution is never wasteful. Females in the traditional roles were responsible for reproduction and the raising of the future generations. Natural selection would have selected out those that had more of their energy and resources diverted to a reproductive and nourishing role for the future generations. Males on the other hand, are selected towards those that are able to pass on their genes through mating. As a hunter and provider, their energy would have been diverted towards greater strength and aggression to bring home the bacon and in order to fend off potential competition for a mate or any threat to his offspring. The ‘side effects’ of an increased risk of cardiovascular disease would have been considered as acceptable part of the package of protecting his genes. These traits are likely have been responsible for many of the gender differences mentioned above in the paper.
Finally, to end off with an interesting thought, could menopause actually be an artefact of medical intervention? Menopause is a relatively new medical condition in the history of mankind. Up to the 1900’s the average life expectancy of an individual was not expected past 50. In the past 100 years, the average life expectancy has increased by an astounding 35 years to 85 for the average female. However, in the past 100 years the average onset of menopause has only increased from the age of 50 to 53. Hence could menopause be actually trying to catch up with our new life expectancy?
Appendix
Fig 1: Death by all causes in women, 2001, UK
The above figure shows the causes of death for all women in the UK in the year 2001. Sources were taken from the Office for National Statistics(2002); General Register Office (2002) Edinburgh, Scotland; General Register Office (2002) Northern Ireland. Picture was obtained from the British Heart Foundation statistics web page. The areas shaded red shows the proportion of death attributed to cardiovascular disease.
http://www.heartstats.org/uploads/documents/FIG%201.3b%20web03%231%23.xls
Figure 2: Ratio of male to female coronary disease mortality per 100 000 population by sex.
The aboge graphs shows the relatively constant linear ratio of relative heart disease rates in men and women in a revirew done on the rate of heart disease death in 52 countires. Reproduced from the clinical review paper by Kalin MF & Zumoff B 1990.
References
Angerer P, Störk S, Kothny W, Schmitt P, & von Schacky C 2001, "Effect of oral postmenopausal hormone replacement on progression of atherosclerosis : a randomized, controlled trial", Arterioscler Thromb Vasc Biol, vol. 21, no. 2, pp. 262-268.
Collins P, Rosano GMC, Sarrel PM, Ulrich L, Adamopoulos S, Beale CM, McNeill JG, & Poole-Wilson PA 1995, "17ß-ostradiol attenuates acetylcholine-induced coronary arterial constriction in women but not men with coronary heart disease.", Circulation, vol. 92, pp. 24-30.
Cullen P, Schulte H, & Assmann G 1998, "Smoking, lipoproteins and coronary heart disease risk", European Heart Journal, vol. 19, no. 11, pp. 1632-1641.
Davis CE, Pajak A, Rywik S, Williams DH, Broda G, Pazucha T, & Ephross S 2002, "Natural menopause and cardiovascular disease risk factors. The Poland and US Collaborative Study on Cardiovascular Disease Epidemiology", Annals of Epidemiology, vol. 4, no. 6, pp. 445-448.
Doll R, Peto R, Wheatley K, Gray R, & Sutherland I 1994, "Mortality in relation to smoking: 40 years' observations on male British doctors", British Medical Journal, vol. 309, no. 6959, pp. 901-911.
Giltay EJ, Hoogeveen EK, Elbers JM, Gooren LJ, Asscheman H, & Stehouwer CD 1998, "Effects of sex steroids on plasma total homocysteine levels: a study in transsexual males and females", The Journal of Clinical Endocrinology and Metabolism, vol. 83, no. 2, pp. 550-553.
Grady D, Rubin SM, Petitti DB, Fox CS, Black D, Ettinger B, Ernster VL, & Cummings SR 1992, "Hormone therapy to prevent disease and prolong life in postmenopausal women", Annals of Internal Medicine, vol. 117, no. 12, pp. 1016-1037.
Herrington DM, Reboussin DM, Brosnihan KB, Sharp PC, Shumaker SA, Snyder TE, Furberg CD, Kowalchuk GJ, Stuckey TD, Rogers WJ, Givens DH, & Waters D 2000, "Effects of estrogen replacement on the progression of coronary-artery atherosclerosis", The New England Journal of Medicine, vol. 343, no. 8, pp. 522-529.
Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, & Vittinghoff E 1998, "Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group", Journal of the American Medical Association, vol. 280, no. 7, pp. 605-613.
Kalin MF & Zumoff B 1990, "Sex hormones and coronary disease: a review of the clinical studies.", Steroids, vol. 55, no. 8, pp. 330-352.
Kesteloot H & Sasaki S 1993, "On the relationship between nutrition, sex hormones and high-density lipoproteins in women.", Acta Cardiologica, vol. 48, no. 4, pp. 355-363.
Larsson B, Bengtsson C, Björntorp P, Lapidus L, Sjöström L, Svärdsudd K, Tibblin G, Wedel H, Welin L, & Wilhelmsen L 1992, "Is abdominal body fat distribution a major explanation for the sex difference in the incidence of myocardial infarction? The study of men born in 1913 and the study of women, Göteborg, Sweden", American Journal of Epidemiology, vol. 135, no. 3, pp. 266-273.
Mosca L, Collins P, Herrington DM, Mendelsohn ME, Pasternak RC, Robertson RM, Schenck-Gustafsson K, Smith SC Jr, Taubert KA, Wenger NK, & American Heart Association 2001, "Hormone replacement therapy and cardiovascular disease: a statement for healthcare professionals from the American Heart Association ", Circulation, vol. 104, no. 4, pp. 499-503.
Parini P, Angelin B, & Rudling M 1997, "Importance of estrogen receptors in hepatic LDL receptor regulation", Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 17, no. 9, pp. 1800-1805.
Porter M, Alder B, & Abraham C 1999, Psychology and sociology applied to medicine Churchill Livingstone, Edinburgh.
Rebuffe-Scrive M, Andersson B, Olbe L, & Bjorntorp P 1989, "Metabolism of adipose tissue in intraabdominal depots of nonobese men and women.", Metabolism, vol. 38, no. 5, pp. 453-458.
Stampfer MJ, Colditz GA, Willett WC, Manson JE, Rosner B, Speizer FE, & Hennekens CH 1991, "Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the nurses' health study", The New England Journal of Medicine, vol. 325, no. 11, pp. 756-762.
Sullivan JM, El-Zeky F, Vander Zwaag R, & Ramanathan KB 1997, "Effect on Survival of Estrogen Replacement Therapy After Coronary Artery Bypass Grafting", American Journal of Cardiology, vol. 79, no. 7, pp. 847-850.
Sullivan JM, Vander Zwaag R, Hughes JP, Maddock V, Kroetz FW, Ramanathan KB, & Mirvis DM 1990, "Estrogen replacement and coronary artery disease. Effect on survival in postmenopausal women", Archives of Internal Medicine, vol. 150, no. 12, pp. 2557-2562.
The British Heart Foundation. Numbers dying from CVD and CHD. The British Heart Foundation. http://www.heartstats.org/datapage.asp?id=713 . 2003. The British Heart Foundation.
Ref Type: Electronic Citation
Verhoef P, Meleady R, Daly LE, Graham IM, Robinson K, & Boers GH 1999, "Homocysteine, vitamin status and risk of vascular disease; effects of gender and menopausal status", European Heart Journal, vol. 20, no. 17, pp. 1234-1244.
Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, & Horwitz RI 2001, "A clinical trial of estrogen-replacement therapy after ischemic stroke", The New England Journal of Medicine, vol. 345, no. 17, pp. 1243-1249.
Woo KS, Chook P, Lolin YI, Cheung AS, Chan LT, Sun YY, Sanderson JE, Metreweli C, & Celermajer DS 1997, "Hyperhomocyst(e)inemia is a risk factor for arterial endothelial dysfunction in humans", Circulation, vol. 96, no. 8, pp. 2542-2544.
Writing Group for the Women's Health Initiative Investigators 2002, "Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the women's health initiative randomized controlled trial.", Journal of the American Medical Association, vol. 288, no. 3, pp. 321-333.
