Clinical Review

Postmenopausal HRT: What is fact, what is fiction?

OBG Manag. 2006 June;18(6):76-85

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Although these findings support the use of estrogen or estrogen-progestin early after menopause as a way of preventing CHD, further clinical trials are needed.⁴⁴

Stroke risk is small but real

Both arms of the WHI found an increased incidence of stroke in women using hormones, compared with nonusers.^16,36 The exact mechanisms underlying this increased risk are unclear.

The actual attributable risk was an increase of 0.7 cases of stroke per 1,000 women per year over placebo in the estrogen-progestin arm,³⁶ and 1.2 cases per 1,000 in the estrogen-only arm.¹⁶ The relative hazards were 1.31 (95% confidence interval [CI] 1.02–1.68) and 1.30 (95% CI 1.10–1.77), respectively.

Note that women in the estrogen-only arm had a greater incidence of hypertension and diabetes mellitus—known risk factors for stroke—than did women in the estrogen-progestin arm.^16,36

VTE risk is twice as high in HRT users

Postmenopausal women who take estrogen have a higher risk of venous thromboembolism (VTE) than those who do not. This risk translated into a relative hazard of 2.06 (1.57–2.70) in the WHI estrogen-progestin arm, or an attributable risk of 3.6 cases per 1,000 women, compared with 1.8 cases per thousand in the control group.³⁶

The absolute increased risk is 1.8 cases per 1,000 women, or, as expressed in the study itself, 18 cases per 10,000 women per year.

I have deliberately reduced the attributable risk to the number of cases per thousand because I believe this number is more easily understood by the patient and accurately demonstrates the low risk.

In the estrogen-only arm of the WHI, the hazard ratio for VTE was 1.33 (0.99–1.79), or an absolute increased risk of 0.7 cases per thousand—although this finding was not significant. The attributable risk was 2.7 cases per 1,000 women, compared with 2.0 cases per thousand among controls.¹⁶

Like stroke, the risk of VTE may be confounded by other factors besides use of exogenous estrogen.

No cause and effect for HRT and breast cancer

Nothing frightens women as much as breast cancer, and articles focusing on the relationship between breast cancer and HRT have drawn widespread attention. However, despite voluminous literature, the etiology of breast cancer remains elusive—and there is no evidence that either estrogen or progestins cause the disease.^45,46 Rather, there is only an association between the use of estrogen, progestin, and breast cancer. Linking the finding of an increased risk with an implication of causality would be inappropriate.

Breast cancer risk with HRT is not consistently elevated, in studies

In fact, a qualitative review of observational studies from 1975 to 2000 found no significant increase or decrease in the risk of breast cancer with estrogen or estrogen-progestin in 80% of the reports.⁴⁷

Risk factors for breast cancer (TABLE 1) include family history, obesity, late childbirth, and hormone therapy—but obesity and family history have higher relative risks than the use of HRT.⁴⁸

TABLE 1

Relative risk of breast cancer

CHARACTERISTIC	RELATIVE RISK
2 family members with breast cancer	14
1 family member with breast cancer	2.2
Obesity	1.8
Young age at menarche	1.6
Hormone therapy	1.3
>30 years of age at birth of first child	1.3
Menopause	0.7

WHI arms find different risks

In the widely publicized WHI, women in the estrogen-progestin arm had an overall relative hazard for breast cancer of 1.24 (95% CI 1.01–1.54), but there was no increased risk in women who had never before used hormones.³⁶ Women who had previously used hormones for 5 years or more did have an increased risk.³⁶ The incidence of breast cancer in the study population was 3 cases per 1,000 women, and the excess number was 0.7 more cases with the use of estrogen-progestin (TABLE 2).

Conversely, in the estrogen-only arm of the WHI,¹⁶ the relative hazard for breast cancer was 0.77 (95% CI 0.59–1.01), and the reduction in risk was almost statistically significant. There are at least 2 potential explanations for the lower incidence of breast cancer in this arm:

Without a progestin, estrogen increases breast density only minimally, allowing for easier mammographic interpretation.
Women susceptible to breast cancer because of their previous use of estrogen may not have been present in the at-risk population in sufficient numbers to cause an increase.

Neither explanation—separate or combined—fully explains the lowered risk in this population. Each population studied appears to have a different level of risk based on multiple factors that cannot be controlled completely in clinical trials and observational studies.

TABLE 2

Extra cases of breast cancer, by risk factor

RISK FACTOR	BREAST CANCERS DIAGNOSED OVER 20 YEARS FROM AGES 50 TO 70 (PER 1,000)	EXTRA BREAST CANCERS (PER 1,000)
Never used HRT	45	-
>5 years HRT	47	2
>10 years HRT	51	6
>15 years HRT	57	12
Late menopause (age 60)	59	14
Alcohol (2 drinks/day)	72	27
No daily exercise	72	27
Weight gain (>20 kg)	90	45
Reprinted from THE LANCET, Vol. 350: 1047–1059, Collaborative Group on Hormonal Factors in Breast Cancer, Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Copyright 1997, with permission from Elsevier