Many healthcare professionals have been asking for the opinions and/or responses of menopause experts to the recent JAMA article.
My comments echo those of my colleague, Dr. Alan Altman, as well as those of Wulf Utian, MD, founder and long-time executive director of the North American Menopause Society who recently stepped down from that post after 30 years.
- This is from the same WHI Study (2002) with one drug, Prempro, in one dose only, given to women average age 63.5 years with a body mass index (BMI) of 28.5 (significantly overweight) when the study began, age 68.5 years with the increased BMI of 30 upon its conclusion 5 years later (obese, a significant increase in risk for breast cancer). The wrong drug, in the wrong doses, to the wrong women. Yet misleadingly presented as if the results applied to the newly menopausal symptomatic women, which they do not.
- This study has absolutely NO impact on you if you are not taking Prempro! That means none of my patients are represented in this study.
- As the WHI has previously shown years ago, and repeated in this study, there is a very small increase in the risk of occurrence of breast cancer when taking Prempro, which as of late did not reach statistical significance (important detail to understand). This small increase was not seen in the Premarin (estrogen-only) part of the study. In fact, in the Premarin-only part of the study, regardless of their age, the women who were greater than 80% compliant with their use of the drug… meaning they took their dose as they were supposed to… had a statistically significant 23% decreased risk of breast cancer!
- This emphasizes once again that something about the progestin used in Prempro, called MPA, helped cause the small increase in breast cancer not seen in the Premarin-only arm. This has been shown in many other studies over the past 30 years:
- estrogen alone = no increase in breast cancer risk, likely small decrease in risk
- estrogen plus MPA = small increase in breast cancer risk (8/10,000 women years of getting diagnosed, 1/10,000 excess breast cancer death attributed to PremPro with 11 years of use shown in this current data set)
This is another small but important reason why most clinicians do not use MPA (Provera brand name) any longer, and haven’t for some time (due to slightly adverse effects on risk markers for heart disease and a slight increase in breast cancer as well).
Natural progesterone (brand name Prometrium) has NOT been shown to elevate risk for breast cancer when used with estrogen. - The increase in the risk of death from breast cancer while taking Prempro compared to placebo, in this newest report, was one woman per 10,000 women per year…a level described as “extremely rare” by the FDA.
- Every study adds a piece to the big picture. The big picture emerges over time, with all ages of women, body types and life styles to create a deeper understanding of benefits and risks; the real associations or outcomes over time. Unfortunately, the media treats each piece as a compelling new revelation, creating confusion and potential for panic. In discussing this study, there has been little media attempt to put it into context so women can better understand the whole picture of risk vs. benefit of taking this drug or any other Hormone Therapy (HT) for menopause. Benefits of HT, shown in WHI and many other studies prior to as well as since WHI, in the appropriate women using the appropriate doses of the appropriate HT begun at the appropriate time, include a decreased risk of heart attack (by far the biggest killer of women each year), diabetes, osteoporotic fracture, colon cancer, and the risk of dying from any cause at all (total mortality). These potential benefits are above and beyond the symptom relief of hot flashes, joint pains, night sweats, sleep disorders, palpitations, headaches, low mood, low libido, vaginal dryness and pain with intercourse commonly associated with menopause. A watermelon sized benefit, a watermelon seed sized risk when prescribed appropriately.
- Within this context of risk vs. benefit, as with any medication or drug, a woman can properly discuss her own individual situation with her doctor or nurse practitioner and make educated decisions without the fear and panic that come from sensationalized news reports and media coverage.
- There is a growing body of data demonstrating that the use of non-oral estrogen, via patch, gel, or vaginal ring, is safer to use than estrogen pills by mouth, taking away the risk of blood clots, and stroke from blood clots, seen with the pills used in WHI, as well as other benefits.
- Talk with your clinician when time allows and remain confident that this “new” Prempro story is likely not to be of any meaningful significance to you. Your quality of life is very important and should be carefully addressed at all stages of your life. Over 50 years of excellent observational data on newly menopausal women in the US, Canada, Great Britain and Europe, billions of women years of use, are not invalidated by this or any other study.
Wulf Utian response
What is it about the WHI writing team that they can take data that they agree is not statistically significant, then reach the unjustified conclusion that with hormones as used in the WHI study, “breast cancer mortality also appears to be increased with combined use of estrogen plus progestin,” and finally through their lead author and others advise women that HT is really dangerous?
So what are the facts?
As with the initial publications, this longer follow up approximately 7 years after the original WHI EPT trial termination in July 2002, confirms a slight increase in incidence of breast cancer in women on combined continuous estrogen plus progestin therapy compared to placebo. Again, as in the first reports, there was a greater incidence of node positive cancers. The original reports confirmed no increase in overall all-cause mortality, but did not report separately on breast cancer deaths. At first blush, this paper would seem to be one leading to more banner headlines against use of postmenopausal hormone therapy, reporting that “breast cancer mortality also appears to be increased with combined use of estrogen plus progestin.” However, one needs to read the paper carefully. There were 25 deaths in the HT group and 12 deaths with the placebo. The HR (hazard ratio) was 1.96 which is almost a doubling of the relative risk (I can just see the headlines – HT doubles risk of dying in postmenopausal women). But the CI (confidence interval) was 1.00-4.04. This wide spread includes 1.00 which makes the difference NOT statistically significant. Hence their statement in their conclusions that mortality “APPEARS to be increased.” For this reason it is totally appropriate to look at the absolute risk. This turns out to be 2.6 vs. 1.3 deaths per 10,000 women per year. By the WHO CIOMS classification, even if this was statistically significant, the increased risk would be classified as extremely rare.
So what do I take away from this? Firstly, the combined continuous use of estrogen plus progestin (at least the products used in the WHI) have an adverse effect on the breast, slightly increasing both the incidence of BC and possibly the chance of dying from it. While this increased risk is rare, it is mandatory on health providers to try “to do no harm” (Hippocratic oath). Fortunately, the good news is that the same WHI investigators just reported at the Asia-Pacific Menopause Society meeting in Sydney that estrogen when administered alone appears to have the opposite effect. That is, they apparently reported that the E alone group had a lower incidence of BC and mortality from BC compared to placebo. I await that publication with interest (but where and when will WHI publish good news?).
Secondly, the NIH and their WHI Writing Group should finally come out with a revised “Global Health Index” targeted specifically at the 50-59 year old group of women because they are the most likely to suffer from severe hot flashes and be prescribed hormones. If benefit on heart, bone, colon, diabetes, and possibly brain is taken into account, the balance of benefit to risk is likely to be quite different from all their previous looks at that score.
The conclusion is therefore that at least the progestin (MPA – medroxyprogesterone acetate) used in the WHI study is not beneficial to the breast and may cause harm. Other studies appear to indicate that alternate progestins or progesterone used in lower doses and intermittently may be safer, but there are no other studies of the size of the WHI and never likely to be.
Bottom line is that after all the hullabaloo over the past 9 years since the initial termination of the HT arm of the WHI, estrogen turns out to be quite safe, the MPA has a cloud of suspicion, and the future recommendation is for careful assessment on an individual basis for every women transiting menopause to determine health status, future risk for disease, and a decision based on a clear indication whether hormones are truly needed and recommended in her situation. If the affirmative, then current knowledge should be used to determine what dose, type, and route of administration should be used.
The WHI has succeeded finally in showing that postmenopausal hormone therapy has clear risks and rewards. The risks are rare, and it is up to every women for herself to decide based on a transparent explanation to her about the facts.
May I conclude that there is no better source for her to get these facts in a clear and unbiased way than from the NAMS website at www.menopause.org.
NAMS response