Hormone Replacement Therapy: Making Sense of all the Hoopla

So you're entering menopause and dealing with the frustrating symptoms that come along with the "change of life". Your doctor has suggested trying hormone replacement (HRT), but every day you are hearing that HRT can lead to breast cancer and other health problems. While there are downsides to HRT, short-term HRT use for relief of menopausal symptoms CAN be an option for some women. Let's review the issues surrounding HRT.

HRT was first introduced in the mid-1970s, based on health benefits including menopausal symptom relief, as well as prevention of cardiovascular disease and osteoporosis. These thoughts were based on the idea that few women had heart disease or osteoporosis prior to menopause, when levels of estrogen were high. Once estrogen levels dropped after menopause, these problems began to emerge. The risk of breast cancer and endometrial (uterine) cancer was thought to be outweighed by these benefits of HRT. Furthermore, the results of numerous small "observational" studies supported these benefits, including the large Nurses' Health Study. These observational studies "watched" or followed women using HRT, but researchers felt it would take a large randomized trial to reveal the true risks involved. Two large randomized, controlled trials have revealed significant risks to HRT use. These studies are the Heart and Estrogen / Progestin Replacement Study (HERS) and the Women's Health Initiative (WHI).

The HERS Study was completed in the late 1990s and included over 2,700 women followed for 4.1 years. The results found that despite improvements in the lipid profile [decreased LDL (bad cholesterol) and increased HDL (good cholesterol)], there was no difference in the number of myocardial infarctions (heart attacks) in the HRT group compared to the placebo (no medication) group. The study period was short, and there was a question as to whether longer use of the hormones would have ultimately resulted in fewer cardiac events.

The largest randomized study looking at the issue of breast cancer risk with hormone replacement therapy (HRT) is The Women's Health Initiative (WHI), a long-term (15 years) national health study sponsored by the National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI). The study focuses on strategies, one of which was taking HRT, for preventing heart disease, breast and colorectal cancer, and osteoporosis in postmenopausal women. Over 161,000 women aged 50-79 are participating in this study, which started enrolling in 1993 and continues to follow these women. The study consists of several groups (or arms); the two that pertain to this article are women taking estrogen alone (those who have had a hysterectomy), and women taking estrogen and progestin. Estrogen alone can have negative effects on uterine tissue, so any woman who still has her uterus (has not had a hysterectomy) is given progestin to counteract this estrogen effect.

The study arm that received estrogen alone was ended early (in March, 2004, after 6.8 years), because not only was there no benefit in preventing heart disease, but there was in fact an increase in blood clots and strokes. The researchers did see a trend towards fewer cases of breast cancer, and this was confirmed after an analysis in 2006. Despite this, the women taking estrogen alone were more likely to have larger tumors if they did develop breast cancer, and more likely to have abnormal mammograms that required follow-up. One interesting theory to explain why fewer women developed breast cancer in this arm is that the women who had their uterus removed may have also had their ovaries removed, a procedure which can decrease breast cancer risk by as much as 50-70%. This still needs to be investigated further.

The estrogen and progestin (E+P) arm was stopped in July 2002 after 5.2 years (also earlier than planned), again because the apparent risks outweighed the benefits. Specifically, the E+P arm experienced more heart attacks, strokes, and blood clots. Furthermore, this arm had a 24% increase in cases of breast cancer (245 of the 8,506 E+P women, compared to 185 of the 8,102 women on placebo, were diagnosed with breast cancer). Although the breast cancer seen in both groups was of similar subtypes under the microscope, the E+P group had larger tumors and more advanced (later stage) breast cancers. The study will continue to follow all of the women for at least 10 more years, so more information is still to come. Of note, this study was looking at the most commonly used hormonal preparation, 0.625 mg conjugated equine estrogens plus 2.5 mg medroxyprogesterone (Premarin®), so we cannot apply these findings to other preparations of estrogen. You can learn more about the Women's Health Initiative at www.whi.org

The United Kingdom conducted a study that followed women 50-64 years of age for 5 years. These women were not randomized, but rather the researchers just observed their HRT use and health. The study was called The Million Women Study because it followed over one million women. The researchers observed a significant increase in breast cancer cases in women taking HRT, as well as an increase in deaths due to breast cancer. Because this study did not compare the women to a placebo group, it is not as reliable as the two previously described studies. You can learn more about this study at www.millionwomenstudy.org

Reviews of all available studies (called meta-analysis) have found significant benefits to HRT in the prevention of osteoporosis and fractures after 5 years of therapy, meaning long-term use would be necessary for prevention. The WHI study pointed to lower incidence of colon cancer in the E+P group, but if these women were later diagnosed with colon cancer, it was likely to be larger or more advanced, thus outweighing any benefit to prevention with HRT. The risk of breast cancer was seen after 5 years in the WHI study and after 10 years of use in the Nurses' Health Study, so short-term use may be okay.

As for cardiac events, the combined study results found that women taking combined HRT (estrogen plus progestin) have higher risks of myocardial infarction (heart attack) and venous thromboembolism (blood clots) after one year of use and stroke after three years.

But don't stop there! The results of a study can only be accurately applied to the type of people who participated in the study. The average age of women in the WHI study was 63, and these women had not taken hormones upon entering menopause. The average age of menopause in the U.S. is 51, and this is the age when most women would be starting HRT. Well, this sure presents a pickle for the average woman considering HRT ! Researchers have reanalyzed the data for younger women in the Nurses' Health Study, finding a decreased risk of cardiovascular disease in women who started the HRT within 4 years of menopause, but no benefit if HRT was started 10 years after menopause. The WHI had too few younger women to make any conclusions, but did hint to a benefit to HRT use in younger women.

So now what? Well, two new studies are looking at HRT use related to cardiovascular risk in younger women. The Kronos Early Estrogen Prevention Study (KEEPS) and The Early versus Late Intervention Trial with Estradiol (ELITE) are underway. There seem to be more questions than ever for women. The bottom line is, HRT can be used in some women for the prevention of menopausal symptoms for short periods of time. Each woman considering HRT for this purpose needs to discuss the risks and benefits with her healthcare provider, keeping her specific health history in mind. Women who wish to use HRT to prevent cardiovascular disease should consider one of the previously discussed clinical trials, which would include risk evaluation and close monitoring. For the prevention of osteoporosis, other agents should be considered, including SERMS (see below), increased calcium and vitamin D intake, and weight-bearing exercise.

On a good note, a group of compounds known as Selective Estrogen Receptor Modulators (SERMS) are being studied in the prevention of breast cancer and osteoporosis. These compounds bind to estrogen receptors (which are found in females in the tissue of the breast, uterus, brain, bone, liver, and heart). SERMS can bind to selected tissue receptors, causing either an anti-estrogen effect OR an estrogen-like effect, depending on the compound. Two commonly used SERMs are tamoxifen and raloxifene (Evista®), which have an anti-estrogen effect on breast and uterine tissue but an estrogen-like effect on bone (which helps prevent osteoporosis). Both compounds have been shown in studies to decrease breast cancer risk, but they have a risk of blood clots, do not help with menopausal symptoms, and do not appear to decrease a woman's risk of heart disease. The Study of Tamoxifen and Raloxifene (STAR) trial is ongoing and should provide us with more information on these 2 compounds in the next few years. You can learn more about the STAR trial at www.nsabp.pitt.edu/STAR/