Human Reproduction, Vol. 18, No. 8, 1561-1563,
August 2003
© 2003 European Society of Human Reproduction and Embryology
Issues to debate on the Women’s Health Initiative
Estrogen: an instrument or the conductor of the orchestra?
Department of Obstetrics and Gynecology County Teaching Hospital and Institute of Clinical and Nurse Sciences, University of Pécs, Faculty of Health Sciences, H-7623 Pécs, Rákóczi u.2., Hungary
1 To whom correspondence should be addressed. E-mail: bodisj@freemail.hu
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Abstract |
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 Top Abstract IntroductionCardiovascular diseases and HRTReproductive age, menopause and...ConclusionsReferences |
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Although it is well known that cyclic production of sex hormones is essential to establish reproductive function and female characteristics, distant impacts of the activity of the female endocrine system result from a concert of delicate mechanisms. Estrogen is rather an instrument than a conductor in this physiological orchestra of the female. Thus, controversies in the explanation of results from studies on hormone replacement therapy (HRT) and cardiovascular disease (CVD) prevention might be eliminated, if we analyse not only the role of estrogen but a broader spectrum of factors leading to CVD. Authors would like to hypothesize that haemorheological changes in women around menopause, such as increased blood and plasma viscosity, haematocrit and fibrinogen, are largely responsible for the increased mortality in the post-menopausal life period. We believe that a cyclic withdrawal bleeding establishes a more favourable haemorheological condition, thus, sequentially administered estrogen might be protective in post-menopausal women. Nevertheless, other factors, that decrease blood viscosity, such as daily exercise, intake of ample amount of fluids as well as ideal nutrition, are equally important. We are confident that sequential HRT, as well as healthy life style and risk prevention programmes have their proper place in the management of this issue.
Key words: cardiovascular disease/haematocrit/HRT/menopause
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Introduction |
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TopAbstractIntroductionCardiovascular diseases and HRTReproductive age, menopause and...ConclusionsReferences |
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Hormone replacement therapy (HRT) has been widely used among post-menopausal women, and recently, besides advantages, drawbacks have been emphasized and potentially dangerous changes in menopause have been attributed to HRT. For this reason, several long-term trials have been set up to clarify the issue. The Women’s Health Initiative (WHI) study clearly demonstrated several negative effects of HRT, such as increased risk of breast cancer, coronary heart disease (CHD) or venous thromboembolism (Rossouw et al., 2002
). These results and the conclusions drawn from them inspired experts of a broad medical panel to share their views, thus igniting further debate on the issue (Beral et al., 2002; Barlow, 2003). |
Cardiovascular diseases and HRT |
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Cardiovascular disease (CVD) is the leading cause of death among women in industrialized countries; >50% of post-menopausal women will die of CVD. Estrogens have been hypothesized to protect against atherosclerosis because the incidence of CVD is low before menopause. Prospective cohort studies generally show that the use of estrogens reduces the incidence of CVD. The Nurses Health Study (Stampfer et al., 1991
), the largest cohort study following 48 000 post-menopausal women for up to 10 years identified 405 cases of nonfatal myocardial infarction or fatal coronary artery disease. The relative risk of coronary artery disease with estrogen use was reduced significantly to 0.89 for ‘ever’ used and 0.53 for current use. Even women at low risk for CVD had significantly less CVD if they received estrogens. Multiple alternative mechanisms for the protective action of estradiol have been proposed including prevention of the oxidation of low density lipoproteins (LDL), increasing prostacyclin levels and decreasing thromboxane levels, thus inducing vasodilatation.
However, the Framingham Study (Eaker et al., 1987), a notable exception, demonstrated an adverse or no effect of estrogen treatment, depending on how CVD was defined and which multiple-regression model was used. This suggests that estrogens may not be the only factor protecting the premenopausal women against CVD.
The article of Tunstall-Pedoe demonstrates a delayed rise in coronary deaths in women compared with men (Tunstall-Pedoe, 1998). Also, it shows that the absolute difference in risk of CHD between men and women continues to increase with age and never closes. The author of that article emphasizes that there is no rebound acceleration in CHD in women at, and after, the menopause. However, data from the same article show that the number of coronary deaths follows the same curve in women as that of men but shifted to higher values of age by about 10 years. It is easy to see that the development of conditions ending up in death from CHD is a process unfolding for many years until it causes clinically significant damage to the cardiovascular system. In fact, statistics demonstrating a delayed rise clearly reflect the fact that the cardiovascular system is exhausted earlier in men than in women, so the 30–35-year reproductive period has a protracted beneficial effect on the cardiovascular status for about 10–15 more years. In our opinion, the widening gap of absolute difference in risk of CHD between the two sexes also demonstrates that the lack of a comparable 30 year ‘female type’ reproductive period in the male has a long term negative effect on the cardiovascular system. We also believe that the appropriate evaluation of any relationship between HRT and death rates from CHD is to be analysed by comparing HRT-user and non-user post-menopausal women instead of comparing the two sexes.
Cardiovascular diseases and haemorheology
The Stockholm Study (Bottiger et al., 1973) of risk factors for myocardial infarction showed that in subjects aged <60 years, those with a haemoglobin in the top quintile had twice the incidence of new coronary events compared with the remaining 80%. More recently in the Puerto Rico Study (Sorlie et al., 1981) of 8700 men followed for 8 years, clinical evidence of myocardial ischaemia was more than double in the high haematocrit (>0.49) than low haematocrit group (<0.42). A similar result was found in a study of 8000 Japanese men followed for 10 years (Carter et al., 1983). A six-fold increase in mortality was also recorded by Burge et al. (1975) in patients with a haematocrit of >0.50. Clinical evidence suggests that a high packed red cell volume may be a primary risk factor in cardiovascular diseases. The threshold level for potentially hazardous haematocrit is around 0.50. The ratio of the incidence of cardiovascular complications for haematocrit values above and below this level is approximately 2:1. Most groups believed to have relatively low risk of cardiovascular disease, such as pre-menopausal women, vegetarians and sportsmen, also exhibit a relatively low haematocrit value and possibly other favourable haemorheological properties. To recognize that a relatively higher haematocrit could be dangerous and should draw medical attention, we should accept that the ‘normal’ range of a physiological variable does not necessarily correspond to the ‘optimal’ one. Haemorheological abnormalities have been found in patients with acute myocardial infarction (Jan et al., 1975; Di Perri et al., 1979). Analysis of the various haemorheological components showed that there were significant increases of haematocrit, plasma viscosity and red cell aggregation in acute myocardial infarction, as compared with the normal control.
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Reproductive age, menopause and haemorheology |
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TopAbstractIntroductionCardiovascular diseases and HRTReproductive age, menopause and...ConclusionsReferences |
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Fluctuations in the circulating levels of estrogen and progesterone, in concert with many other factors, are responsible for normal menstruation. Normal menstrual cycles are 28 ± 7 days (mean ± SD) in length with a duration of flow of 4 ± 2 days and menstrual blood loss of 40 ± 20 ml. This monthly recurrent physiological blood loss results in about 15–20% difference in haematocrit values between men and women during reproductive age, resulting in a more favourable haemorheological condition in women, thus a lower risk of CVD. After menopause, in the absence of menstrual blood loss, the lowered haematocrit of women is equalized continuously up to the male level. Woodward et al. (1999
) published that men exhibit higher levels of blood viscosity and haematocrit than do women. Accordingly, post-menopausal women had higher blood viscosity, haematocrit, corrected blood viscosity, plasma viscosity and fibrinogen levels than pre-menopausal. Also, mean haemoglobin was lower in premenopausal women than in post-menopausal women (P < 0.0001) (Milman et al., 2001). There are data on haemorheological changes during HRT demonstrating a decreased plasma viscosity and erythrocyte rigidity (Frohlich et al., 1998; Spengler et al., 2003). These findings appear to be in contradiction with the CHD outcome in the WHI trial. However, it is important to note that in the WHI trial, estrogen and progestin were continuously administered during the 5-year follow-up period. Beside that, we have to emphasize that, in addition to any change in plasma viscosity, another key event in haemorheology after menopause is the increase of the haematocrit value. It is inarguable that this parameter is shifted toward a more advantageous range when cyclic withdrawal bleeding is achieved. Thus, contrary to the WHI trial, we believe, that, the optimal manner of administering HRT is sequential, which maintains monthly withdrawal bleeding. Unfortunately, there are not yet data on CHD and other risks available from studies on sequential HRT for a longer term. |
Conclusions |
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TopAbstractIntroductionCardiovascular diseases and HRTReproductive age, menopause and...ConclusionsReferences |
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Summarizing the above data we can draw a conclusion that significant haemorheological changes associated with menopause may contribute to the increased cardiovascular risk observed in post-menopausal women (Hinderliter et al., 2002
). Therefore, we propose all kinds of ‘intervention’ to keep haemorheological properties within the favourable range following menopause. These may include HRT in a sequential manner causing cyclic withdrawal bleeding and leading to lower haematocrit levels. Also, the importance of appropriate life style should be emphasized, involving daily exercise, intake of ample amount of fluids as well as ideal nutrition. We are confident, that, within this wide range strategy, hormone replacement should receive its proper place, and this opinion could be further supported by results of multicentre studies focusing on the detailed issue.
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Acknowledgement |
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We are grateful to the Hungarian Ministry of Health for their support (ETT: 36309).
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References |
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TopAbstractIntroductionCardiovascular diseases and HRTReproductive age, menopause and...ConclusionsReferences |
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Barlow, D.H. (2003) Time to reflect on the Women’s Health Initiative (WHI) Study. Hum. Reprod., 18, 1–3.
Beral, V., Banks, E. and Reeves, G. (2002) Evidence from randomised trials on the long-term effects of hormone replacement therapy. Lancet, 360, 942–944.[CrossRef][Web of Science][Medline]
Bottiger, L.E. and Carlson, L.A. (1973) The Stockholm prospective study.2.Skandia Int. Symposia: Early phases of coronary heart disease. Nordinska Bokhandelns.Forlag, Stockholm, pp.158–181.
Burge, P.S., Johnson, W.S. and Prankerd, T.A.J. (1975) Morbidity and mortality in pseudopolycythemia. Lancet, 1, 1266–1269.[Medline]
Carter, C., McGee, D., Reed, D., Yano, K. and Stemmermann, G. (1983) Hematocrit and the risk of coronary heart disease: The Honolulu Heart Program. Am. Heart. J., 105, 674–679.[CrossRef][Web of Science][Medline]
DiPerri, T., Forconi, S., Guerrini, M. and Rossi, C. (1979) Blood viscosity in the different stages of ischemic heart disease. In Angina Pectoris and Myocardial Infaction, International Congress Series no. 491, Excerpta Medica, Amsterdam-Oxford-Princeton, pp.348–353.
Eaker, E.D. and Castelli, W.P. (1987) Coronary heart disease and its risk factors among women in the Framingham study. In Eaker, E.D., Packford, B., Wenger, N.F., Clarkson, T.B., Tyroler, H.A. (eds) Coronary heart disease in women. Haymarket Doyma, New York, pp.122–130.
Frohlich, M., Schunkert, H., Hense, H. W., Tropitzsch, A., Hendricks, P., Doring, A., Riegger, G. A. and Koenig, W. (1998) Effects of hormone replacement therapies on fibrinogen and plasma viscosity in postmenopausal women. Br. J. Haematol., 100, 577–581.[CrossRef][Web of Science][Medline]
Hinderliter, A.L., Sherwood, A., Blumenthal, J.A., Light, K.S., Girdler, S.S., McFetridge, J., Johnson, K. and Waugh, R. (2002) Changes in hemodynamics and left ventricular structure after menopause. Am. J. Cardiol., 89, 830–833.[CrossRef][Web of Science][Medline]
Jan, K.M., Chien, S., Bigger, J.T.Jr (1975) Observation on blood viscosity changes after acute myocardial infarction. Circulation, 51, 1079–1084.
Milman, N., Byg, K.E., Mulvad, G., Pedersen, H.S. and Bjerregaard, P. (2001) Haemoglobin concentrations appear to be lower in indigenous Greenlanders than in Danes: assesment of haemoglobin in 234 Greenlanders and in 2804 Danes. Eur. J. Haematol., 67, 23–29.[CrossRef][Web of Science][Medline]
Rossouw, J. E., Anderson, G. L., Prentice, R. L., LaCroix, A. Z., Kooperberg, C., Stefanick, M. L., Jackson, R. D., Beresford, S. A., Howard, B. V., Johnson, K. C. et al. (2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA, 288, 321–333.
Sorlie, P.D., Garcia-Palniery, M.R., Costas, R. and Havlik, R.J. (1981) Hematocrit and risk of coronary heart disease: The Puerto Rico Heart Program. Am. Heart. J., 101, 456–461.[CrossRef][Web of Science][Medline]
Spengler, M. I., Goni, G. M., Mengarelli, G., Bravo, L. M., Bocanera, R., Tozzini, R. and Rasia, M. L. (2003) Effect of hormone replacement therapy upon haemorheological variables. Clin. Hemorheol. Microcirc., 28, 13–19.[Web of Science][Medline]
Stampfer, M.J., Colditz, G.A., Willett, W.C., Manson, J.E., Rozner, B., Speizer, F.E. and Hennekens, C.H. (1991) Postmenopausal estrogen therapy and cardiovascular disease: ten-year follow-up from the Nurses’ Health Study. N. Eng. J. Med., 325, 756.[Abstract]
Tunstall-Pedoe, H. (1998) Myth and paradox of coronary risk and the menopause. Lancet, 351, 1425–1427.[CrossRef][Web of Science][Medline]
Woodward, M., Rumley, A., Tunstall-Pedoe, H. and Lowe, G.D. (1999) Associations of blood rheology and interleukin-6 with cardiovascular risk factors and prevalent cardiovascular disease. Br. J. Haematol., 104, 246–257.[CrossRef][Web of Science][Medline]
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