Risks of hormone therapy

Any discussion of HT risks must include the baseline risks of women not using HT or ET (Figure 10.2). Table 10.4 outlines the probability that a menopausal woman will develop chronic disease Another useful perspective maybe gained by comparing these risks with risks from some common everyday activities (Table 10.5). One out of 100 women who use HT for one year will experience a net additional adverse outcome compared with non-users. Safer preventive strategies for most chronic conditions are available. Table 10.6 lists the additional adverse outcomes of 10 000 women EPT users for each year of use. There were 19 excess events in the women using EPT, or a 1% five-year risk. Of 200 women who use HT for five years, one woman will not have an osteoporotic fracture or colorectal cancer. Four will develop invasive breast cancer, CHD, stroke, or venous thromboembolism.13

Table 10.4 Estimated lifetime risk for US women of developing certain conditions or dying

% of women who will develop condition Lifetime probability

Table 10.4 Estimated lifetime risk for US women of developing certain conditions or dying

% of women who will develop condition Lifetime probability


over lifetime

of dying







Hip fracture


Breast cancer


Endometrial cancer


Colorectal cancer


Dementia (75-84 years of age)*


Osteoporosis after 80 years of age


Motor-vehicle collision


Air travel


Dog bite

1/234 896

* 7-8% of individuals 75-84 years of age have dementia; postmenopausal women have a 1.4-3.0 higher risk of Alzheimer's disease than do men.

Source: National Safety Council, National Center for Health Statistics, US Census, Women's Health Sources, Mayo Clinic.

Table 10.5 Risks of death per 10 000 women each year by condition


Mortality rate per 10 000 women per year





Automobile driving


Continuing a pregnancy


Cardiovascular disease

HT is not recommended for either primary or secondary prevention of coronary heart disease. In the WHI study, seven additional women had heart attacks for every 10 000 women who used both estrogen and progesterone for

one year.13 Stroke

HT appears to increase the risk of stroke. The Nurses' Health Study demonstrated a dose-response relationship, with the risk of stroke increasing in women who used higher hormonal dosages. In the Group Health Cooperative

Table 10.6 Outcome of 10000 women who use EPT for one year

Reduction in cases of the following conditions among 10 000 women who use EPT for one year

Increase in cases of the following conditions among 10 000 women who use combined EPT for one year

Hip fractures


Heart attacks


Colon cancer




Invasive breast cancer




emboli/deep vein

Source: Nelson, H. D., Humphrey L. L., LeBlanc, E.; et al. Postmenopausal Hormone Replacement Therapy for Primary Prevention of Chronic Conditions. Summary of the Evidence. http://ahrq.gov/clinic/3rduspstf/hrt/hrtsum1.htm. Accessed August 21, 2002.


Source: Nelson, H. D., Humphrey L. L., LeBlanc, E.; et al. Postmenopausal Hormone Replacement Therapy for Primary Prevention of Chronic Conditions. Summary of the Evidence. http://ahrq.gov/clinic/3rduspstf/hrt/hrtsum1.htm. Accessed August 21, 2002.

Study, the risk of stroke was not associated with the current use of estrogen and progestin. However, the risk of stroke increased two-fold during the first six months of hormone use, and the risk of ischemic stroke increased with the dose of estrogen.14 The stroke risk also increased in the WHI study.

Thrombotic events

Risks for thromboembolic events are highest in the first two years of use. A woman using HT has a risk approximately four-fold greater than that of a non-user. After the first year or two, the risk decreases but remains double that of non-users. The risk of thromboemoblism may also display a dose-response effect.15

Breast cancer

Breast cancer has been linked increasingly to the use of HT. Previous analyses have suggested a 15% increase in breast cancer for women using estrogen plus progestin for less than five years and a greater than 50% increase in risk for duration of HT for more than five years.16 The HERS study reported a 27% increase in breast cancer after 6.8 years of use.17

Some studies suggest an increased risk when EPT was used compared with estrogen alone. Studies of women who had ever used HT, as opposed to studies of current HT users, did not find an increased rate of breast cancer. All six cohort studies that looked at breast cancer mortality demonstrated no effect or decreased mortality among women who had ever used HT or who had used HT for less than five years. Two studies that reported results for use longer than five years yielded conflicting results. The review concluded that benefits include fewer fractures and lower rates of colon cancer, and suggested fewer cases of dementia, which was classified as an "uncertain benefit." Harms included increased numbers of CHD events, strokes, thromboembolic events, breast cancer, and cholecystitis.18

The increased risk of breast cancer associated with HT decreases to that of non-users five years after HT was discontinued.19 Risk may vary by cancer histology. HT maybe associated with less aggressive and less advanced types of breast cancer.20 In the WHI study, the risk of invasive breast cancer was increased by 26% (38 versus 30 per 10 000 woman per year). No significant difference was observed for in situ breast cancer. Increased breast cancer risk did not appear during the first four years of use.21

The risk of breast cancer increases with duration of use. If 100 women begin HT at 50 years of age, then the excess numbers of breast cancers diagnosed are two new cancers after five years of use, six new cancers after 10 years of use, and 12 new cancers after 15 years of use. This risk appears to dissipate five years after HT is discontinued.22 The evidence on breast cancer mortality in longer-term users is mixed.23,24 Although the incidence of breast cancer appears to be increased with HT, most studies do not demonstrate that breast cancer mortality is increased in ever-users or short-time users of HT.25 One study has even demonstrated a reduced risk of death from breast cancers in HRT users.26

Endometrial cancer

Unopposed estrogen, the administration of estrogen alone, in women with a uterus increases the risk of endometrial cancer. Progestin given in addition to estrogen decreases this risk. Some studies suggest that the progestin must be given for more than 10 days a month.27,28 Typical regimens give progestin in a low dose daily, as a continuous dose, or cyclically for 12-14 days per month. No definitive studies conclude that a progestin-containing intrauterine device can substitute for an oral progestin or whether the progestin dose can be given less frequently. No studies have compared the long-term safety of various progestin options.

The risk of endometrial cancer appears to be increased with duration of use and remains elevated five years following discontinuation. The risk may vary depending on the type of estrogen product used and is greater in women using conjugated versus synthetic estrogen.

In addition, women who use unopposed estrogen, an estrogen preparation without progesterone, are more likely to develop endometrial carcinoma if their uterus has not been removed. A meta-analysis of 29 observational studies demonstrated a relative risk of 2.3 for estrogen users compared with nonusers, with 95% confidence interval 2.1-2.5. Increased risk was associated with increasing duration of use. Risk remained elevated five or more years following discontinuation of estrogen therapy. Conjugated estrogens were associated with a greater risk than synthetic estrogens. Endometrial cancer mortality was not elevated.29

Ovarian cancer

Studies linking HRT or ERT to ovarian cancer have been inconclusive.30,31 One study followed 211581 postmenopausal women from 1982 to 1996. Those with ten or more years of estrogen use had an increased risk of dying from ovarian cancer. The risk decreased after HT was discontinued but persisted at a higher level than in never-users.32 Other studies seem to relate the risk of ovarian cancer to duration of use.33

Cognition and dementia

At the present time, HT is not recommended as primary or secondary prevention for Alzheimer's disease (AD).34 Animal models have suggested biologically plausible mechanisms by which estrogen might be protective against neurodegenerative conditions such as AD.35 The prevention of AD is particularly important for women since they are at increased risk of developing AD compared with men. Results from case-control studies and two prospective studies have been mixed. One study36 and a meta-analysis37 reported as much as a 30% reduced risk of AD in women who report ever using HRT compared with non-users.

Of the studies that suggest a benefit, most demonstrate a decreased risk or delay in onset of AD in postmenopausal women using HT (primary prevention) but no effect of estrogen on the clinical course of AD in women with mild to moderate established disease (secondary prevention).38 Other studies, such as that of Seshadri and colleagues,39 demonstrate no benefit in AD prevention with over ten years of HT use. A more recent prospective study40 reported a decreased incidence of AD in women who used HT for ten or more years. These women did not display the anticipated increased gender risk of AD. Their adjusted risk of AD was half that of non-users. Most of the current users used unopposed estrogen (estrogen without a progestin). Nine RCTs of HT and cognition demonstrated improvement in verbal memory, vigilance, reasoning, and motor speed only among symptomatic women (with menopause-related cognitive symptoms), but not among those who were asymptomatic.41 WHI and HERS have not reported effects of HT on cognition and dementia.

Several large RCTs on the effects of estrogen therapy on women at risk for AD are under way, including the Women's Health Initiative Memory Study (WHIMS) and the WHI Study of Cognitive Aging. These studies will examine whether ET given to women aged 65 years or older (not from the time of menopause) prevents or delays AD.

Another major study, the Women's International Study of Long Duration Oestrogen after Menopause (WISDOM), which had enrolled more than 5000 of a planned 16 000 women in England, Australia, and New Zealand and was scheduled to continue until 2016, was ended prematurely in October 2002 following the review of WHI results.42 Raloxifene may enhance memory in women with AD,43 but additional research is needed.44

Diabetes mellitus

Data from the HERS found that women who used EPT (daily treatment of 0.625 mg conjugated estrogen and 2.5 mg medroxyprogesterone acetate) had a 25% lower risk for developing type 2 diabetes mellitus over four years of follow-up in women who were predominately white.45 This is consistent with the results from earlier studies and has been more consistent with oral as opposed to transdermal estrogens. To date, no RCT design to test this hypothesis has been conducted.


The Nurses' Health Study reported a relative risk of 1.8 for cholecystitis for HT users compared with non-users. The risk increased with duration of use and remained elevated when HT was discontinued. HT is associated with one additional case per 250 users/year of symptomatic cholecystitis.46

Other adverse events

HT is far from a panacea for all women.47 Many women never fill the initial prescription. Those who fill it initially often discontinue use because of side effects, including irregular bleeding, fluid retention, breast tenderness, headache, nausea, and dry eyes. As many as 30-40% of women experience some degree of abnormal bleeding in the first year of use. Weight is not usually affected.



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