Safety Issues with HRT

• known or suspected pregnancy
• known or suspected breast cancer
• estrogen-dependent neoplasia
• undiagnosed abnormal genital bleeding
• active thromboembolic disorders

Ongoing research, however, suggests that some of these contraindications may not be absolute. In the meantime, all the relative contraindications must be carefully discussed with patients and weighed against the risk of not prescribing HRT, especially for women with CVD. If HRT is inappropriate, other options should be considered that are specific for each patient's risk of disease.

This is also a good time to discuss the common concerns that women have about HRT. The multiple benefits of long-term postmenopausal hormone therapy represent an attractive preventive healthcare option for most women. But safety concerns may cause many women to discontinue, or not initiate, therapy. The most common of these issues is fear of breast cancer. Helping patients understand the true risk of breast cancer, and the true contribution of HRT, is critical.

Women have a lifetime risk of developing breast cancer of about 1 in 8.(46) The risk of developing breast cancer increases with a woman's age. But it is also related to her decade in life. For example, a woman who is 40 years of age has a 10% risk of developing breast cancer by the time she reaches 80. A woman who is 70, however, has only a 4% risk of developing breast cancer by the time she reaches 80.(81)

White non-Hispanic women have the highest incidence rate for breast cancer among racial and ethnic groups in the United States (Figure 12).(82) But African American women have the highest mortality rate for breast cancer. Although there has been an increase in the overall incidence of breast cancer among all women, mortality rates have not increased (Figure 13).(83) Part of the explanation for this is that breast cancer is being diagnosed earlier (carcinoma in situ), at a time when treatment is more likely to be effective.(84,85)

Figure 12

Figure 13

Mammography for Early Detection

• National Cancer Institute (NCI)
• Every 1 to 2 years for women in their 40s
• Every 1 to 2 years for women aged 50 and over
• Women who are at higher than average risk of breast cancer should seek medical expert advice about the frequency of screening and whether they should begin screening before age 40.
• American Cancer Society (ACS)
• Every year beginning at age 40
• American College of Obstetricians and Gynecologists (ACOG)
• Every 1 to 2 years for women in their 40s
• Every year for women aged 50 and older According to the NCI, early detection messages may be particularly important for several minority groups that include:
• African American women – they have the highest mortality and lowest survival rates for breast cancer
• Hispanic women – breast cancer incidence rates are increasing faster among Hispanics than other women
• American Indian or Alaska Native women – they have higher breast cancer incidence rates and lower survival rates than some other groups of women.
• Asian or Pacific Islander women – some studies suggest that their cancer rates increase as they become acculturated

Breast Cancer Studies

Over 50 studies have examined the relationship between ERT/HRT and breast cancer. The RR scale in Figure 14 shows there is no clear trend in regard to such an association.(90-100) Nursing literature draws a similar conclusion.(15,68) One 10-year, prospective double-blind study that investigated breast cancer and estrogens found no increase in breast cancer risk with estrogen therapy.(101) None (0/84) of the estrogen-treated women (2.5 mg of conjugated equine estrogen po qd and MPA 10 mg po qd for 7 days per month) developed breast cancer compared to 4.7% (4/84) of those who did not receive HRT (P <.061). The study suggested that the addition of progestin to HRT did not seem to increase breast cancer risk.

Figure 14

At the end of the 10-year study, a follow-up study began. Patients were given the option of continuing, discontinuing, or starting estrogen therapy. Those who chose estrogen took 0.625 mg po qd and MPA 10 mg po qd for 10 days per month. This follow-up lasted another 12 years, resulting in a 22-year study with 3271 patient years. It showed that patients treated with estrogen had no increased risk of developing breast cancer.(102) None of those receiving HRT (0/116) developed cancer, while 11.5% never users (6/52) did develop breast cancer (P <.001). Even among several meta-analyses, there does not appear to be an increase in breast cancer risk in women taking estrogen replacement therapy.(91,103-107) Several points arising from the studies were noteworthy. Looking at all women who had ever used estrogen, either currently or in the past, showed that ERT had no effect on breast cancer risk.

A number of these studies altered the analysis to examine the effect of duration of estrogen use. Increasing duration produced a slight increase in RR of breast cancer that was inconclusive. Also, there was no consistent association of ERT and breast cancer risk in patients with a family history of benign breast disease.

A recent reanalysis of epidemiological data on more than 160,000 women from 51 investigation centers showed an increase in risk of breast cancer with HRT.(108) Ever use (both current and former use combined) had a RR of 1.14, current HRT use had a RR of 1.35, and former use was associated with a RR of 1.07. The RRs for ever and current use were based on a factor of 2.3% increase/year of use and were statistically significant. The size of the study is noteworthy (the conclusions are based on 17,949 cases of breast cancer), but a closer look may be warranted given the unexpected nature of its findings.

There was a lack of agreement and uniformity among the centers. In addition, the study produced inconsistent results about duration: the group using hormones for 10 to 14 years had no statistical evidence of an increase in risk (RR 1.09). The RR was decreased for former users, which is inconsistent biologically. Moreover, the conclusion that current and recent users had evidence of only localized disease suggests bias. Less aggressive tumors and better survival rates in hormone users may suggest earlier detection. Despite the discrepancies among numerous studies, there is no clear, compelling evidence for an association between estrogen replacement therapy and breast cancer. In general, women must be given information about what current studies indicate and the fact that there is no clear trend.

Then, it is the responsibility of healthcare professionals to help them make a decision about HRT that is comfortable for them.

Family History

There is little or no evidence to support the common perception that a family history of breast cancer contraindicates HRT. A recent study (Table 11) found that there was no significant increase in breast cancer with hormone use among women with a such a family history.(109) There was, however, a significant reduction in total mortality. Such a benefit in overall mortality has also been found among women who use ERT/HRT in general.

Table 11

The study detailed in Figure 15 found that mortality from any cause among women postmenopausal women who used ERT/HRT was lower than among nonusers.(110) The survival benefits were most apparent for current users (RR 0.63, CI = 0.56-0.70), and were greatest for coronary heart disease (RR 0.47, CI = 0.32-0.69). The protective effect of hormones persists for 3 to 4 years after therapy is stopped but is lost after 5 years. Among short-term users of therapy, there was a significant reduction in breast cancer risk (past RR 0.83, CI = 0.63-1.09 and current RR 0.76, CI = 0.56-1.02). Moreover, in a subgroup of women with a family history of breast cancer, the RR was 0.65, CI = 0.47-0.90.

Figure 15

HRT and Women Who Develop Breast Cancer

In one of these studies that involved 6000 women, the relative survival rate was significantly higher (P = 0.02) by about 10 percentage points at 8 years in women who had received HRT.(111) This higher survival advantage was found only in women over the age of 50 and was most pronounced in recent HRT users, that is, patients who had discontinued hormone therapy less than 1 year prior to diagnosis.

Although the use of HRT in women who have a history of breast cancer is controversial, there is also evidence that these women may benefit from such treatment after diagnosis in terms of recurrences and death.(115-119)

Summary Of Breast Cancer Issues

Other Safety Issues

It has been demonstrated in a number of studies that the addition of progestins to ERT clearly reduces the risk of endometrial cancer to that of never-users.(124,125) The most current of the studies that demonstrates this found a RR of 5 (1.6-5.9) for women who took estrogen only (Table 12).(124) However, the relative risk of endometrial cancer was only 0.9 (0.7-1.2) among those who received estrogen and progestin.

Table 12

Another safety issue that has received attention with HRT use is stroke. The majority of studies have found that estrogen therapy has no effect on risk of stroke (Figure 16). Wilson et al, the Framingham Study, reported an increased risk of stroke among postmenopausal hormone users, but confidence intervals were not calculated.(126) Four of these 5 studies found that HRT lowered the risk of stroke in postmenopausal women.(127-130)

Figure 16

There has also been some concern about primary pulmonary embolism (PE) with estrogen. A classic study found an increased risk of PE with current HRT use among postmenopausal women.(131) The risk is diminished, however, with past HRT use. Primary PE was uncommon in this population of healthy women.

One final safety issue with estrogen that has received some attention is deep venous thromboembolism (DVT). Two studies found an increased risk of DVT among current hormone users.(132,133) However, one of these studies reported that the increased risk may be concentrated in new users, and the other suggested that the absolute risk was low and accounted for only a modest risk in mortality. A third study found no increased risk with HRT at all.(134) Raloxifene carries the same risk for DVT as estrogen.

Estrogen, as part of HRT, is a comprehensive therapy that offers benefit to the majority of menopausal women. When risks and benefits are weighed, it is appropriate therapy that offers both short-term and long-term benefits. For the perimenopausal women, HRT counseling must go beyond symptom control to include prevention of heart disease and osteoporosis. Control of body weight and of alcohol and tobacco consumption, encouragement of regular exercise, maintenance of mental health including sexuality, and cancer screening are other counseling issues. Nurses are in a unique position to help women make the choice that is right for them.