Issues to debate on the Women’s Health Initiative study

Failure of estrogen plus progestin therapy for prevention of breast cancer risk

T. Luukkainen

Institute of Biomedicine, Biochemistry, Biomedicum Helsinki, P.O. Box 63, FIN-00014 University of Helsinki, Finland. e-mail: Tapani.Luukkainen{at}helsinki.fi


    Abstract
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 Abstract
 Introduction
 Breast cancer
 Incidence of coronary heart...
 Comments and recommendations
 References
 
Several studies on hormone replacement therapy (HRT) in the USA have been published. They revealed that the risk of breast cancer is increased with HRT more than with estrogen alone (ERT). A progestin has been given with each dose of ERT, as was the case in the Women’s Health Initiative (WHI) study. The results of studies in Europe show similar trends. The increased risk of breast cancer in the WHI study was significantly higher only in women who had used HRT for several years before entering the study. The study was non-blind in 3444 cases, i.e. 40.5% of women in the estrogen plus progestin group and 6.8% in controls. If the women in the HRT group had more mammographic examinations it could change the validity of the results of the study. Estradiol-containing drugs have now been added to the list of carcinogens and the packages of these drugs have warning labels. The results of the WHI study do not support this labelling. The results of the WHI study show that the administration of HRT increases the risks of stroke and pulmonary embolism. It is reasonable to think that in the case of bleeding, at least at weekends in nursing homes (when staff levels may be low) patients were immobilized in their beds. Immobilization among women on HRT could have been more dangerous than the HRT itself. Progestins need to be delivered to the endometrium in a manner that will have the least effect on the breast. Systemic administration can be replaced by releasing progestin locally in the uterine cavity. Endometrial protection with a levonorgestrel-releasing intra-uterine system (IUS) is well tolerated. The high hepatic concentrations of estrogens given orally could be avoided by transdermal administration. New studies should be planned to reflect the situation in clinical practice. The time to start HRT in healthy menopausal women is between the ages of 45 to 55 years.

Key words: breast cancer/estrogen/HRT/progestin


    Introduction
 Top
 Abstract
 Introduction
 Breast cancer
 Incidence of coronary heart...
 Comments and recommendations
 References
 
The Editorial of Human Reproduction in the January 2003 issue (Barlow, 2003Go) covers the points of view of a number of investigators on the results of the Women’s Health Initiative (WHI) Study. The results were published in July 2002 (Writing Group for Women’s Health Initiative Investigators, 2002Go). The press interest was dramatic and the study’s impact exceeded the limits of its results.


    Breast cancer
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 Abstract
 Introduction
 Breast cancer
 Incidence of coronary heart...
 Comments and recommendations
 References
 
Several studies on hormone replacement therapy (HRT) in the USA have been published during the last 5 years. They revealed that the risk of breast cancer is increased with HRT more than with estrogen alone (ERT). These studies have been cited in the WHI study report (Writing Group for Women’s Health Initiative Investigators, 2002Go) and in an editorial (Fletcher and Golditz, 2002Go). The progestin has been given in a sequential fashion or with each dose of ERT (continuous-combined HRT), as in the WHI study (Writing Group for Women’s Health Initiative Investigators, 2002Go). The results of studies in Europe show similar trends (Berkvist et al., 1989Go; Magnusson et al., 1999Go). A very recent case–control study from the USA revealed that continuous combined HRT was associated with an increased breast cancer risk among current users >=5 years. However, there was no positive association between breast cancer risk and other HRT regimens (Weiss et al., 2002Go).

The main progestin used in these studies has been medroxyprogesterone acetate (MPA) in the USA, and in Europe nortestosterone derivatives have been used as well (Magnusson et al., 1999Go). The estrogen components in the USA have almost exclusively been conjugated equine estrogens, and in Europe the estrogen component has been estradiol valerate. The increased risk of breast cancer in the WHI study was significantly higher only in women who had used HRT for several years before entering the study (Sitruk-Ware, 2003Go). Women using continuous-combined HRT had poor bleeding control and therefore the study was non-blind in 3444 cases, i.e. 40.5% of women in the estrogen plus progestin group. The study does not reveal if these women underwent more breast examinations than the controls, of whom only 6.8% were non-blind to the medication. If the women in the HRT group had more mammographic examinations it could change the validity of the results of the study.

The WHI study did not reveal any correlation between the risk of breast tumours and body mass index (BMI), as reported in a large study earlier (Schairer et al., 2000Go). These authors found an increased risk of breast cancer in leaner women, BMI <=24.4 kg/m2, who had HRT. Women with a high BMI had a high risk that was not increased significantly by HRT or ERT. In the WHI study, 34% of the women treated with HRT had a high BMI; >30 kg/m2. The short duration of the study indicates that breast cancer is not caused by the introduction of HRT during the study. The combination of estrogen and MPA, however, could affect the growth of an existing undetected cancer (Sitruk-Ware, 2003Go). If the results of the WHI study on breast cancer risk are valid, they still only indicate the risk associated with continuous combined HRT (see Weiss et al., 2002Go).

The estrogen-alone arm of the study will be continued to March 2005. The same estrogen dose as given daily in combined HRT in women who have had an hysterectomy has not caused safety problems (Writing Group for Women’s Health Initiative Investigators, 2002Go). Estradiol-containing drugs have now been added to the list of carcinogens and the packages of these drugs have warning labels. The results of the estrogen arm of the WHI study have not been published and do not support the labelling.


    Incidence of coronary heart disease and cardiovascular disease
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 Abstract
 Introduction
 Breast cancer
 Incidence of coronary heart...
 Comments and recommendations
 References
 
In ovariectomized monkeys on an atherogenic diet, ERT, and ERT plus progesterone, are able to prevent coronary heart disease (CHD) (Adams et al., 1990Go; see also Barlow 2003Go). Estrogen replacement therapy, and HRT with norethisterone or levonorgestrel are effective in reducing aortic accumulation of cholesterol in rabbits (Haarbo et al., 1991Go). Could it be that the type of the progestin and/or the route and dose of its administration in HRT are important? Studies in women show the lack of curative action of ERT and HRT on the progression of coronary artery atherosclerosis. Herrington et al. (2000Go) studied 309 women with angiographically verified coronary artery disease. They were randomized to receive (i) Premarin (conjugated equine estrogen), 0.625 mg daily, (ii) Premarin, 0.625 mg and Provera (MPA), 2.5 mg daily (a similar regimen to that used in the WHI study), and (iii) placebo. The mean age of the women was 66 years. Significant effects on lipids were observed: low density lipid (LDL) reduction and high density lipid (HDL) increase with ERT and HRT. However, there were no significant effects of ERT or HRT over a period of 3.2 years in minimal diameter or stenosis as evaluated by angiography. Furthermore, there were no clinical differences during the first year or during the whole study in CHD events, or death for any reason, or death because of CHD. It seems that the observed effects on lipids, as in this study, cannot explain the reduction in heart disease seen in observational studies. The reduction of LDL concentrations and the increase of HDL levels are not as beneficial and curative as has been proposed in CHD. There is also accumulating evidence that statins have beneficial effects in CHD independent of their classical actions on lipoproteins (MacFarlane et al., 2002Go).

In observational studies, ERT and HRT have been started at an early stage in perimenopausal women for prevention, and not late for curative action as in the WHI study (Writing Group for Women’s Health Initiative Investigators, 2002Go), where the mean age was 63 years. The results of the WHI study show that the administration of HRT increases the risks of stroke and pulmonary embolism. These are known side-effects of ERT, but have not yet been seen more in women having estrogen only than in women taking placebo. In the WHI study the women treated with continuous combined HRT had poor control of bleeding. They had no special counselling and they did not understand that the treatment caused bleeding. It is reasonable to think that in the case of breakthrough bleeding, at least at weekends in nursing homes (when staff levels were reduced) they were immobilized in their beds. We know that also in men a relatively short period of immobilization during intercontinental flights increases the risk of pulmonary embolism and stroke. Immobilization among women on HRT could have been more dangerous than the HRT itself. The risks of osteoporotic fractures were significantly reduced, showing that in bone tissue estrogen is curative, also when given together with MPA.


    Comments and recommendations
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 Abstract
 Introduction
 Breast cancer
 Incidence of coronary heart...
 Comments and recommendations
 References
 
The WHI study (Sitruk-Ware, 2003Go), like several other studies, shows that a high systemic dose of progestin in HRT increases the risk of breast cancer more than is the case with ERT. Pike and Ross (2000Go), in their case–control study, reported an increased risk of breast cancer with HRT versus ERT and the risk increased with the duration of HRT use. They concluded that progestins clearly need to be given to protect the endometrium. Progestins need to be delivered to the endometrium in a manner that will have the least effect on the breast. This can be carried out by using a direct endometrial route of administration.

Systemic administration can be replaced by releasing progestin locally in the uterine cavity. This method of administration has been found to induce rapidly the absence of bleeding in HRT (Andersson et al., 1992Go). Endometrial protection with a levonorgestrel-releasing intra-uterine system (IUS) is well tolerated as a progestin component in HRT with different routes of estrogen administration (Pakarinen et al., 2001Go).

Intrauterine release of levonorgestrel gives a high concentration in the endometrium and a low daily dose and low blood concentration of the progestin. The intrauterine release of levonorgestrel, plus ERT, mimics hysterectomy plus ERT, which in the WHI study (Writing Group for Women’s Health Initiative Investigators, 2002Go) does not appear to be associated with safety problems.

The conjugated equine estrogen preparation Premarin contains several equine metabolites, many of them not found as estradiol metabolites in women. It is difficult to find an estradiol preparation which biologically has exactly the same effect as the equine estrogens in Premarin. More difficult is the comparison with the transdermal route of estrogen replacement. Transdermal ERT has different metabolic effects than the oral route of estrogen administration (O’Sullivan et al., 1998Go). The high hepatic concentrations of estrogens given orally could be avoided by transdermal administration and the results may differ from those in the WHI study as regards the incidence of CHD and cardiovascular complications. There is a need to study these other regimens of HRT, because the WHI study does not give any information on these promising alternatives.

The title of the study indicates that the women involved were ‘healthy’. However, they were relatively old and had many signs of risks associated with CHD such as obesity. The different outcome with estrogen alone in hysterectomized women may be attributed to the fact that they were ‘healthier’, because they were well examined before operation and selected to be risk-free as regards surgery. This could hamper the comparison of HRT and ERT in the WHI study in the future.

It remains the case that there has been no randomized control study carried out to document the effects of other HRT combinations on the health of women. There is a great need to plan further research on the basis of the results of this remarkable pioneer study.

New studies should be planned to reflect the situation in clinical practice. The time to start HRT in healthy menopausal women is between the ages of 45 to 55. The women should be given a ‘health programme’: regular daily exercise, weight control and good cardiological care. There should be effective follow-up with risk markers (Ridker et al., 2002Go) and registered follow-up of compliance with the medication. Women in nursing homes should not be used in studies on HRT for several ethical reasons. In addition, such women are not comparable with women who live normal active lives at home.


    Acknowledgement
 
Dr Nicholas Bolton is gratefully acknowledged for the expert linguistic revision of this manuscript.


    References
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 Abstract
 Introduction
 Breast cancer
 Incidence of coronary heart...
 Comments and recommendations
 References
 
Adams, M.R., Kaplan, J.R., Manuck, S.B., Koritnik, D.R., Parks, J.S., Wolfe, M.S. and Clarkson, T.B. (1990) Inhibition of coronary artery atherosclerosis by 17 beta estradiol in ovariectomized monkeys. Lack of an effect of added progesterone. Arterioscler. Thromb. Vasc. Biol., 10, 1051–1057.[Abstract]

Andersson, K., Mattsson, L.-O., Rybo, G. and Stanberg, E. (1992) Intrauterine release of levonorgestrel: a new way of adding progestogen in hormone replacement therapy. Obstet. Gynecol., 79, 963–967.[Abstract]

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Haarbo, J., Leth-Espensen, P., Stender, S. and Christiansen, C. (1991) Estrogen monotherapy and combined estrogen-progestogen replacement therapy attenuate aortic accumulation of cholesterol in ovariectomized cholesterol-fed rabbits. J. Clin. Invest., 87, 1274–1279.[ISI][Medline]

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Ridker, P.M., Rifai, N., Rose, L., Buring, J.E. and Cook, N.R. (2002) Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N. Engl. J. Med., 347, 1557–1565.[Abstract/Free Full Text]

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Weiss, L.K., Burkman, R.T., Cushing-Haugen, K.L., Voigt, L.F., Simon, M.S., Daling, J.R., Norman, S.A. et al., (2002) Hormone replacement therapy regimens and Breast Cancer risk. Obstet. Gynecol., 100, 1148–1158.[Abstract/Free Full Text]

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