The Women’s Health Initiative (WHI) trials, initiated by the US National Institutes of Health in 1991, marked one of the largest US prevention studies, and set out to investigate the most common causes of death, disability and impaired quality of life in postmenopausal women. The trials looked at cardiovascular disease, osteoporosis and cancer, including the effect of different hormone replacement therapies on breast cancer risk. Surprisingly, women on conjugated equine estrogens (CEE) alone showed a reduced risk, whilst those on CEE plus medroxyprogesterone acetate (MPA) showed an increased risk. Ross Prentice from the Fred Hutchinson Cancer Research Center, USA, and colleagues sought to understand what underlies these divergent results through analyzing differences in blood sex hormone levels, the results of which are published in a recent Breast Cancer Research study. Prentice discusses what they found and what impact this will have on hormone therapy for postmenopausal women.
What led to your research interest in hormone therapy for breast cancer?
The present research arose from a desire to understand the biology underlying the results of the Women’s Health Initiative randomized, placebo controlled trials of the two most commonly used postmenopausal hormone therapy preparations in the United States. The regimes studies were also widely used in the UK and other Western countries.
Your study probed whether sex hormone level changes could explain the divergent results of the Women’s Health Initiative trials into the association between breast cancer risk and postmenopausal hormone therapies. How did this investigation come about?
Conjugated equine estrogens (CEE) include a complex mixture of estrogens, and has a profound effect on blood levels of major estrogens, including an approximate doubling of estradiol and a tripling of estrone, but also an approximate doubling of the offsetting sex hormone binding globulin (SHBG). On the surface it seemed unlikely that these changes, which were very similar for CEE and for CEE plus medroxyprogesterone acetate (CEE+MPA), could both explain an important breast cancer risk increase with CEE+MPA and a breast cancer risk reduction with CEE-alone. However, the blood concentration changes were quite substantial, and we thought it important to examine the extent to which they could explain the clinical trial findings in a formal ‘mediation-type’ analysis.
What were your key findings and were you surprised by them?
We found that the collective changes in blood sex hormones could explain much of the breast cancer reduction with CEE, but none of the increase in risk with CEE+MPA. Evidently, in the population studied, the increase in SHBG with CEE was more than sufficient to compensate for the estrogen increases, yielding a somewhat reduced breast cancer risk. We were surprised to find that for CEE+MPA the substantial variation in breast cancer risk related to pre-randomization circulating sex hormones completely disappeared when a woman used CEE+MPA. It seems likely that the addition of MPA to the treatment regimen resulted in a major stimulation of breast ductal epithelial cells bringing women who were at relatively low risk, perhaps due to favorable diet and activity patterns over the life span, up to a similar breast cancer risk to that for women who were at a relatively high baseline risk.
What kind of impact will the findings have on hormone therapy formulations in the clinic?
There is already much reduced use of CEE+MPA worldwide, based on findings for breast cancer and other diseases from the Women’s Health Initiative and substantial observational studies, such as the UK Million Women’s Study (MWS). The use of CEE has also been reduced, to a lesser extent, since related health benefits and risks are approximately balanced. To avoid risks associated with CEE, that include elevations in stroke and venous thromboembolic disease, there has been a trend toward the use of lower doses of CEE and a trend toward the use instead of transdermal estrogens (i.e. estrogen patch), which bypass the liver and may avoid some of the inflammatory consequences of oral estrogen use. However, transdermal estrogens also do not produce SHBG increases, so any related favorable breast cancer effects may be lost. Further research into the development and evaluation of safe and effective hormone therapy regimens, or alternatives to hormone therapy for the control of menopausal symptoms, deserves a continuing high priority in the biomedical research agenda.
Who is going to be affected by this research?
Women making decisions about hormone therapy will be affected by this research. The sex hormone changes resulting from CEE seem to have rather little overall effect on breast cancer risk. However, many of the women studied in the WHI trials were years past the menopause when randomized, and the breast cancer implications appear to be more favorable for these women , than for women who start CEE near the menopause. In fact, with much larger numbers of women than is available in WHI, the UK MWS finds a breast cancer risk increase with CEE among recently postmenopausal women. Hence a cautious approach to CEE use will continue to be needed among women who are post-hysterectomy, until more is learned about safe and effective regimens. Women with a uterus could wisely avoid the use of MPA among strategies they consider to address vasomotor symptoms.
What’s next for your research?
We are currently trying to more fully understand CEE effects on breast cancer, including some further comparisons of WHI data analyses with published UK MWS results. Also, some WHI investigators have been vigorously studying alternatives to exogenous hormones for menopausal symptom management.