What the Women’s Health Initiative Results Mean for Breast Cancer Survivors

In July 2002 a large, randomized control trial called the Women’s Health Initiative was stopped three years early with the conclusion that Estrogen plus Progestin (E+P) is, on balance, not an effective preventative medication for healthy menopausal women. The results of this trial have surprised both doctors and the general public, because they have shown that E+P does not prevent heart disease and causes breast cancer (1 [1]). We believe there are several changes in concepts about menopausal hormone therapy that are important for breast cancer survivors.

The first change since the results of the E+P study is the knowledge that healthy, naturally menopausal women don’t need any hormone therapy to prevent heart disease. The E+P study showed an increase in heart attacks in those on hormones. Why did we formerly think that estrogen prevented heart attacks? Because the women who took estrogen in the non-randomized studies were healthier and had better lifestyles (2 [1])! The combined results of the past studies and the E+P randomized trial lead to the conclusion that women’s risk for heart attack can be decreased by 80 percent by regular exercise, achieving and maintaining normal weight, not smoking, and treatment of abnormal blood lipids, high blood pressure and blood sugars. That means that breast cancer survivors who avoided estrogen therapy were not missing out on any heart preventive benefits!

The results of the E+P study say that menopause itself does not need treating. However, what has happened when the eight thousand study participants on estrogen plus progestin were told to suddenly stop their hormone therapy is that some developed severe night sweats and hot flushes (vasomotor symptoms, VMS). Now many more women and their doctors appreciate the misery from suddenly stopping estrogen. Many women who became menopausal due to breast cancer treatment already understand this! VMS caused by suddenly stopping estrogen are some of the most intense and difficult to treat.

There are some other recent developments in research on stress, enzymes and hormones that are relevant to breast cancer survivors struggling with hot flushes. Women having intense, persistent, sleep-disturbing night sweats are living with very high levels of adrenal stress hormones (3 [1]), some of which are converted into estrogen by the aromatase enzyme. New results from trials of drugs that inhibit aromatase in breast cancer survivors show improved breast cancer outcomes indicating that this is important. Therefore preventing the production of these stress hormones and the misery of night sweats takes on a new importance for breast cancer survivors.

But, you say, what effective therapies are available to treat hot flushes and night sweats in women with breast caner? The first is to prevent vasomotor symptoms in the first place—never stop estrogen suddenly. All women being treated with estrogen who need to stop it should do it very gradually over about four months. Daily full-dose progesterone therapy (Prometrium 300 mg at bedtime or medroxyprogesterone 10 mg/d) assists in the process of stopping estrogen without causing recurrent hot flushes. The Centre for Menstrual Cycle and Ovulation Research website (www.cemcor.ubc.ca [2]) has information about gradually decreasing and stopping estrogen therapy [3]. Vasomotor symptoms can be improved by stress reduction, and by treatment with progesterone and some progestins.

We believe that there are several important and non-harmful therapies to treat night sweats and hot flushes for the breast cancer survivor. The first is to take up relaxation therapy, yoga breathing (4 [1]) or mind-body therapy. All of these have been shown in controlled trials to improve night sweats and hot flushes. Treatment of depression with an antidepressant will also decrease stress hormones and may help night sweats. The importance of decreasing stress hormones as a treatment for VMS is only now becoming clear. And, given the aromatase inhibitor therapy results, reducing stress hormones should also help prevent breast cancer recurrence.

The second effective therapy for night sweats is progesterone or non-male hormone like progestins (such as medroxyprogesterone or megestrol (5 [1])). A study we did some years ago showed that medroxyprogesterone (10 mg/d) is as effective as conjugated equine estrogen (0.625 mg/d) in control of vasomotor symptoms (6 [1]) Oral micronized progesterone has the added advantage that it assists with sleep (7 [1]).

The next question is, are progesterone or non-androgenic progestins safe for breast cancer survivors? The results of non-randomized trials in the past have suggested that progesterone added to the increased breast cancer risk from estrogen therapy. However, progesterone is used to treat high estrogen side effects such as bleeding and breast tenderness. This means there is a bias in these studies because only women with highest estrogen exposure would be given progestin. Based on better-designed studies, we believe that progesterone is safe for breast cancer survivors.

First, two large studies show that premenopausal women who have too little progesterone (lack of ovulation) but enough estrogen have higher breast cancer risk (8 [1],9 [1]). The strongest data are from two randomized, placebo-controlled studies of the women’s breast cell changes in response to estrogen or progesterone therapy. Briefly, in both studies the breast cells of women who were taking progesterone showed markedly less proliferation (which is associated with increased cancer risk) than the cells of women on estrogen (10 [1],11 [1]). All of these studies are consistent with the idea that progesterone controls the estrogen-related breast cell growth that carries a risk for cancer. Therefore we believe that progesterone is both safe and effective therapy for women breast cancer survivors with severe night sweats that relaxation therapy doesn’t adequately control.

In summary, the results of the first large controlled study of “hormone replacement therapy” for healthy menopausal women provide good news for breast cancer survivors. The first is that good lifestyle, not estrogen treatment prevent heart disease. The second is an increased awareness of the disability caused by severe night sweats that occur when estrogen therapy is suddenly stopped. From other recent studies we now know that the high stress hormones caused by having severe night sweats probably carry an increased risk for women with breast cancer. Finally, from well designed studies we now know that progesterone is both safe and effective therapy for severe night sweats in breast cancer survivors.

References

1. Writing Group for the Women's Health Initiative Investigators: Risks and benefits of estrogen plus progestin in health postmenopausal women: principle results from the Women's Health Initiative Randomized Control trial. JAMA 2002; 288: 321-333.
2. Barrett-Connor E: Postmenopausal estrogen and prevention bias. Ann.Int.Med. 1991; 115: 455-456.
3. Genazzani AR, Petraglia F, Fachinetti F, Facchini V, Volpe A, Alessandrini G: Increase of proopiomelanocortin-related peptides during subjective menopausal flushes. Am.J.Obstet.Gynecol. 1984; 149: 775-779.
4. Freedman RR, Woodward S: Behavioral treatment of menopausal hot flushes: evaluation by ambulatory monitoring. Am.J.Obstet.Gynecol. 1991; 167: 436-439.
5. Quella SK, Loprinzi CL, Sloan JF, et al: Long term use of megestrol acetate by cancer survivors for the treatment of hot flashes. Cancer 1998; 82: 1784-1788.
6. Prior JC, Alojado N, Vigna YM, Barr SI, McKay DW: Estrogen and progestin are equally effective in symptom control post-ovariectomy--a one-year, double-blind, randomized trial in premenopausal women. Program of the 76th Annual Meeting of the Endocrine Society, Anaheim, Ca. 1994; Abstract 12H: 411(Abstract)
7. Friess E, Tagaya H, Trachsel L, Holsboer F, Rupprecht R: Progesterone-induced changes in sleep in male subjects. Am.J.Physiol. 1997; 272: E885-E891
8. Cowan LD, Gordis L, Tonascia JA, Jones GE: Breast cancer incidence in women with a history of progesterone deficiency. Am.J.Epidemiol. 1981; 114: 209-214.
9. Coulam CB, Annegers JF, Kranz JS: Chronic anovulation syndrome and associated neoplasia. Obstetrics and Gynecology 1983; 61: 403-407.
10. Chang KJ, Lee TTY, Linares-Cruz G, Fournier S, de Lignieres B: Influence of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo. Fertil.Steril. 1995; 63: 785-791.
11. Foidart J, Collin C, Denoo X, et al: Estradiol and progesterone regulate the proliferation of human breast epithelial cells. Fertil.Steril. 1998; 5: 963-969.