Tag Archives: Hormone Therapy

The Women’s Health Initiative

It has now been 11 years since the first publications came out using data from the Women’s Health Initiative (WHI).  For anyone who may not have heard of the WHI, it was the largest trial to date on the use of hormone therapy in menopausal woman.  It was designed and overseen by the National Institutes of Health in the US.  The WHI was, in particular, designed to assess the risks and benefits of hormone therapy on prevention of chronic diseases such as heart disease, breast and colorectal cancer, and fractures in postmenopausal women.   In the original publication of the initial results in the Journal of the American Medical Association, the authors state: “This trial did not address the short-term risks and benefits of hormones given for the treatment of menopausal symptoms.” In the study of combined estrogen plus progestin, 16 608 women between the ages of 50 and 79 years were recruited, mean age 63, and started on hormones or placebo.  They stopped this trial after an average of 5.2 years.  In real terms, the findings at that point showed increases over the placebo group of 7 more heart attacks per 10 000 women, 8 cases of breast cancer per 10 000 women, 8 more strokes per 10 000 women and 18 cases of blood clots; there were 6 fewer cases per 10 000 of colorectal cancer, 44 fewer fractures of all kinds per 10 000 women, and 5 fewer hip fractures per 10 000.

The WHI study of estrogen therapy only in postmenopausal women who have had hysterectomies was stopped in 2004 after 6.8 years.  This study included 10739 women between the ages of 50 and 79 who were randomized to treatment with estrogen alone or placebo.  The findings differed from the previous study, and showed 5 per 10 000 fewer cases of CHD, 12 per 10 000 more strokes, 7 per 10 000 more episodes of blood clots, 7 per 10 000 fewer cases of breast cancer, 6 per 10 000 fewer each of hip and vertebral fractures; no difference was seen for colorectal cancer.

The media had a field day publishing articles on the first study BEFORE it was peer-reviewed and analyzed in any further detail.  Of course, all of the articles published reported the above results as relative risks, which are percentages.  For example, this changes the attributable risk of breast cancer of 0.08% per year in these results to an increase in relative risk of 26% (38/30).  The World Health Organization considers 0.08% as a low, if not very low, risk. 26% is downright scary.

Not understanding statistics makes interpretation of scientific study results all the more scary.  I have attended talks where I have heard said there is a lack of statistical literacy in society.  Very few people have a chance to take a course in statistics, much less need to use it daily.  However, it is good to have a general understanding.  For some simple explanations, please see “Statistics for the rest of us” in the general blogs.

The huge database generated by the WHI, which included the study discussed above, and studies on estrogen use alone, in postmenopause, low-fat dietary patterns and calcium and vitamin D supplementation, has been subjected to extensive analysis over the past decade, providing much useful information to research on menopause and disease.

Reassessment of the risk data after stratifying it by age helped to show less risk of heart disease in the 50 to 59 age group, with increased risk in the 60 to 69 and 70 to 79 age groups.  It is now not recommended to start hormone therapy in a woman over 60, as it may increase her heart attack risk.  Several more recent studies have shown that use of hormone therapy around the time of the menopause transition in a woman’s 50s is likely to be protective against heart disease.    This phenomenon is discussed in other sections as the “timing hypothesis” or “critical window”, as well as other monikers.  Although this is not yet considered a reason to prescribe HT, some experts feel that recommendation may yet happen.

Analyses of data from numerous studies have found that a woman’s risk of breast cancer does not increase with the use of less than five years of hormone therapy.  In estrogen and progesterone-receptor positive tumors, hormones are considered to be promoters and not initiators of tumor growth.  This means they may stimulate an existing tumor to grow, but they are not responsible for it starting in the first place.  The recommendations for HT use today are similar to what we knew in the 1990s, with a small increase in risk of breast cancer for longer use of HT.  I have heard it said that a tumor often starts up to six years prior to its detection, although this would obviously be affected by numerous factors.

Thus, the WHI led to a media storm that led to many women discontinuing hormone therapy on the basis of incomplete information.  In medicine and science, information is never “complete”, as we are learning and discovering new things all the time.  It’s time for the media to reassure women that we know differently now.

Statement of Agreement of Hormone Therapy Use, 2012

A joint statement on hormone therapy use prepared by the North American Menopause Society (NAMS), the American Society for Reproductive Medicine (ASRM) and The Endocrine Society was published in July 2012.  The statement has been endorsed by 12 other leading organizations in women’s health.  The major points of agreement were:

• Hormone therapy is an acceptable option for the relatively young (up to age 59 or within ten years of menopause) and healthy women who are troubled by moderate to severe menopausal symptoms.  Decisions to be made on individual basis.
• If women are experiencing vaginal dryness or discomfort with intercourse, the preferred treatments are low dose vaginal estrogen.
• Women who still have a uterus need to take a progestogen (progesterone or synthetic) along with estrogen to prevent cancer of the uterus.  Women who have had their uterus removed can take estrogen alone.
• Both estrogen therapy and estrogen plus progestogen therapy increase the risk of blood clots in the legs and lungs, similar to birth control pills, patches and rings.  Although the risks of blood clots and stroke increase with either type of hormone therapy, the risk is rare in women ages 50 to 59.
• There is an increased risk in breast cancer seen with 5 or more years of continuous estrogen with progestogen therapy, possibly earlier.  The risk decreases after hormone therapy is discontinued.

It has been recommended that women work with their health care providers to assess their personal risks and benefits.  It is recommended that the lowest dose of estrogen that provides symptoms relief be used, and for the shortest duration needed.

The 2012 Hormone Therapy Position Statement of the North American Menopause Society

In addition to the above, NAMS published their most recent position Statement on Hormone Therapy in March, 2012.  Their conclusions and recommendations:

• The decision to use HT should be made individually for each woman based on her health, her quality of life priorities and her personal risk factors for diseases.
• The duration of therapy is different for HT and ET.  HT use should be limited to 3 to 5 years due to increasing risk of breast cancer with longer use.  ET has been shown to have a favorable risk-benefit profile up to 7 years of use and 4 years follow-up.
• ET is the most effective treatment of symptoms of vulvar and vaginal atrophy.  Low-dose, local vaginal ET is recommended when only vaginal symptoms are present.
• Women with premature or early menopause, who are otherwise appropriate candidates for HT can use HT at least until the median age of natural menopause (51 years).  They may use HT longer if needed for symptom management.
• Although ET did not increase breast cancer risk in the WHI, there is a lack of safety data supporting the use of ET in breast cancer survivors; one RCT reported a higher increase in breast cancer recurrence rates.
• Both transdermal and low-dose oral estrogen have been associated with lower risks of VTE and stroke than standard doses of oral estrogen (RCT evidence not yet available at publication time).