Results of the WHI Hormone Replacement Therapy Studies

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Results of the WHI Hormone Replacement Therapy Studies

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Clinical medical practice changed rapidly and dramatically with the results of the two parallel Women's Health Initiative (WHI) studies of postmenopausal hormone replacement therapy (HRT). These were the first large, double-blind, placebo-controlled clinical trials of HRT in healthy, postmenopausal women. The WHI estrogen-plus-progestin trial and estrogen-alone trial were both halted early (in July 2002 and February 2004 respectively) because the health risks of the conjugated equine estrogen and progestin studied exceeded benefits.

The first report on the halted WHI estrogen-plus-progestin study came out in July 2002.. It followed a total of 16,608 women, aged 50 to 79 (average age = 63 at study intake). One arm followed patients for 5.2 years who were either on a combination of the progestin medroxyprogesterone acetate and conjugated equine estrogens (8506 women) or a placebo (8102 women). The WHI study found that the measured risks of this combination outweighed its measured benefits (see the table, below). The results were almost universally reported as risks and problems associated with HRT in general, rather than with the specific proprietary combination of conjugated equine estrogen and progestin studied.

Adverse event

Relative risk
(95% CI)

Change in number of events
per 10,000 women in one year

Breast cancer

1.26 (1.00-1.59)

8 more

Heart disease

1.29 (1.02-1.63)

7 more


1.41 (1.07-1.85)

8 more

Pulmonary embolism

2.13 (1.39-3.25)

8 more

Colorectal cancer

0.63 (0.43-0.92)

6 fewer

Hip fracture

0.66 (0.45-0.98)

5 fewer

The cardiac results of the above WHI study of estrogen plus progestin were age specific. The participants' average age was 63, and the overall results were as shown above. The blending of younger and older women in the study obscures possible cardiac benefits of HRT in women who begin HRT at the younger end of the range of 59 - 79 of the study participants. In the estrogen + progestin study, women who were less than 5 years postmenopausal showed a trend toward reduced heart disease risk (relative risk = 0.89, 95% CI 0.5-1.7). For the subset of women who were age 50-59 in the WHI estrogen-alone study, an even stronger trend was observed towards a reduced risk of cardiovascular disease (relative risk = 0.56, 95% CI 0.30-1.03) but neither trend was statistically significant. No increase in stroke risk was observed in the younger women in the latter study (relative risk for stroke = 1.08, 95% CI 0.57-2.04).

The adverse cardiovascular outcomes observed in the WHI study may not apply to other forms of estrogen replacement therapy such as topically administered estradiol and estriol. Results from other studies suggest that when estrogen is administered orally, liver function is altered and the risk of blood clots is increased .

In the preliminary 2004 results of the WHI estrogen-alone clinical trial there was an observed trend, that was not statistically significant, towards a reduced risk of breast cancer (relative risk = 0.77, 95% CI 0.59-1.01). In a recently published 2006 update of the WHI estrogen-alone study, researchers concluded that use of estrogen-only HRT for 7 years does not increase the risk of breast cancer in postmenopausal women who have had a hysterectomy. The results of the WHI estrogen-alone trial suggest that the progestin used in the WHI estrogen-plus-progestin trial increased the risk for breast cancer above that associated with estrogen alone. Hormone replacement therapy with estrogen alone ("unopposed estrogen") poses unacceptable cancer risks to women who have not previously had a hysterectomy.

After the increased clotting found in the first WHI results was reported in 2002, a large number of women who had been taking the proprietary mixtures of equine estrogens and progestins studied (PremPro) quit refilling their prescriptions. Some simply stopped all hormones, and others switched to bioidentical hormones. The number of PremPro prescriptions filled was abruptly cut almost in half.

A study by M.D. Anderson reported in a medical conference in San Antonio Texas in December 2006 looked at new cancer diagnoses in the U.S. in 2003, the year following the initial reports of clotting in connection with use of PremPro. A staggering 7% drop in new diagnoses of breast cancer in the U.S. was noted in 2003, compared with 2002 levels. One third of the decrease could have been related to a reduced number of mammographies. But the balance appeared to be related to widespread cessation of PremPro use. Reductions were by far the sharpest in women over 50, the age group among whom prior PremPro use (and thus discontinuation) was most likely. This and other studies suggest that the shift away from the proprietary PremPro combination was a key factor. These studies are consistent with the possibility that replacing PremPro with bioidentical hormones could reduce cancer risks. Long-term use of hormone combinations other than PremPro has already been found to be associated with lowered incidence of cancer. For example a large 2004 population study of women who used birth control pills found a reduced risk of heart disease and stroke and an overall decreased risk of cancer. In this study, women who had used birth control pills at some point in their lives were noted to have an 8% lower risk of heart disease, no increased risk of breast cancer, and a 7% lower overall cancer risk including significant reductions in ovarian and colon cancer. This 2004 study of the contraceptive pill's protective effects followed smaller studies that had found a slight breast cancer promotion associated with use of certain oral contraceptives. The favorable picture of contraceptive benefits emerged from the 2004 study's analysis of the very large body data collected from the over 160,000 women who had participated in the Women's Health Initiative study.

see: U.S. Hormone Replacement Therapiesfor a chart of hormone replacement therapies available in the United States, and UK Hormone Replacement Therapiesfor a chart of hormone replacements available in the United Kingdom. These charts do not yet include Elestrin, a fast-drying gel formulation of bio-identical estradiol approved by the U.S. Food and Drug Administration in December 2006, at dosages of either 0.87-gram or 1.7-gram. Although the 0.87 gram dose is 50% less than the next lowest dose of estradiol currently on the market, in studies it has provided significant relief of menopause symptoms to 80% of its users.

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