HRT, Estrogen, and Postmenopausal Women: Year-Old WHI Study Continues to Raise Questions

Pharmacology Watch
The Women's Health Initiatives (WHI) was halted 1 year ago, but fallout from this landmark study continues. The study was designed to identify the risks or benefits of estrogen plus progesterone vs placebo in healthy postmenopausal women. More than 16,000 women were randomized to a fixed dose of conjugated estrogen 0.625 mg plus medroxyprogesterone 2.5 mg daily. The second arm of the study randomized women who had undergone hysterectomy to conjugated estrogen alone vs placebo. The combination estrogen/progesterone wing of the study was halted prematurely and results published in July 2002 when the overall risk of intervention with combination estrogen/progesterone was found to outweigh benefits. Specifically, the risk of breast cancer hit a predetermined threshold in the intervention group, and study was halted after only 4 years. The main outcomes included increased risks of coronary heart disease, stroke, and venous thromboembolic disease, as well as an increased risk of invasive breast cancer. The hormone combination did result in a lower risk of colorectal cancer and a decreased risk in hip and vertebral fractures. All-cause mortality was the same in both groups (JAMA. 2002;288:321-333). The second wing of the study, looking at estrogen alone, is continuing with implication that the same level of adverse events was not seen in this arm of the study. The total duration is planned to be 8.5 years.

WHI and Dementia

WHI data continue to be analyzed and published. Most recently, combined estrogen/progesterone was found to increase the risk of probable dementia in women aged 65 and older and did not prevent mild cognitive impairment in the same group. Another study in the same journal found that estrogen/progesterone did not improve cognitive function in women 65 and older, and in fact led to a clinically meaningful cognitive decline in some women on the combination therapy. A third study in the same journal confirmed findings published last July that combination estrogen/progesterone increases the risk of ischemic stroke in generally healthy postmenopausal women (JAMA. 2003;289:2651-2662,2663-2672,2673-2684).

Alternative Therapies

Concern that oral fixed dose conjugated estrogen/medroxyprogesterone may have more deleterious effects than benefits has sent primary care doctors and their patients scrambling for alternatives. Currently, most experts are recommending hormone replacement therapy only for severe menopausal symptoms and only for a short interval after menopause. But many questions remain. What should be done with women who have had a hysterectomy and are on unopposed estrogen? Are other estrogen/progesterone combinations safer than conjugated estrogen/medroxyprogesterone? Is transdermal estrogen safer? Or should all hormones be avoided and alternatives sought?

Oral Estrogen and CRP Levels

A recent study suggests, for example, that oral, but not transdermal, estrogen elevates levels of C-reactive protein (CRP), which has been associated with myocardial infarction and other adverse outcomes. In a small study, 21 postmenopausal women were randomized to 8 weeks of daily treatment with transdermal estradiol 100 mg or oral conjugated estrogen 0.625 mg or placebo in a crossover fashion. Transdermal estrogen had no effect on CRP or insulin-like growth factor, while oral estrogen more than doubled CRP levels and significantly reduced levels of insulin-like growth factor. The authors suggest that since CRP is synthesized in the liver, oral estrogen may stimulate its production, whereas transdermal estrogen, which bypasses enterohepatic circulation, does not elevate CRP. They further suggest that since CRP is a powerful predictor of adverse prognosis in otherwise healthy postmenopausal women, the route of administration of estrogen should be considered when prescribing HRT (J Am Coll Cardiol. 2003;41:1358-1363). And while the WHI showed an increase in vascular events in women on conjugated estrogen/medroxyprogesterone, it was the increase in the rate of breast cancer that led to the early termination of the study. New data suggest that the progestin in the combination of hormones may be associated with a greater risk of breast cancer than estrogen. A review of the records of nearly 30,000 Swedish women in the early 1990s revealed that combined continuous HRT was associated with a 4.6-fold increase in the risk of breast cancer compared to women who never took HRT (95% CI, 2.39-8.84). The breast cancer rate for estrogen-only HRT was 1.89 (not significant; 95% CI, 0.80-5.56) (Cancer. 2003;97: 1387-1392). The eventual publication of the estrogen-only wing of the WHI, which is ongoing, will help to further elucidate this important issue.

Discontinue Unless Used Short-Term

Meanwhile, most national experts are recommending discontinuing estrogen/progesterone unless it is being used in a short-term fashion to treat severe vasomotor symptoms. Many postmenopausal women have elected to follow these recommendations, and many women entering menopause are electing not to start HRT in the first place. The vasomotor symptoms, especially hot flashes, are the most consistently bothersome postmenopausal symptom, but unfortunately there are no non-HRT treatments that are consistently effective. Some patients try "natural" remedies such as isoflavones found in soy protein, or black cohosh. And while there is no doubt that isoflavones have some estrogenic activity, the risks vs benefits of these products are still unknown. Newer options include SSRI antidepressants—especially paroxetine, fluoxetine, and sertraline. A recent paper from the Mayo clinic even suggests that gabapentin may be helpful (Mayo Clin Proc. 2002;77:1159-1163).

Alendronate Viable Option for Bone Loss

Many women who recently discontinued HRT were taking it specifically for protection against osteoporosis. Studies have shown that bone loss accelerates within the first year of stopping HRT. Alendronate may be a viable option for some women according to a new study sponsored by Merck. The study enrolled 144 women who were on HRT for least 1 year, had been postmenopausal for at least 3 years, and had discontinued HRT within the last 3 months. Patients were randomly assigned to alendronate 10 mg/d or placebo. Treatment with alendronate was associate with 82.3% mean increase in spine bone mineral density (95% CI, 1.7-3.0) compared with the mean loss of 3.2% in patients receiving placebo (95% CI, -4.6 to -1.7). Increases in hip and total body bone mineral density were also observed with alendronate, which was well-tolerated (Arch Intern Med. 2003;163:789-794). Other options for preventing and treating osteoporosis in postmenopausal women include the other bisphosphonate risedronate, calcitonin nasal spray, the selective estrogen receptor modulator (SERM) raloxifene, the recently approved parathyroid hormone-like agent teriparatide, and the old standbys of vitamin D and calcium.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. Telephone: (404) 262-5517. E-mail: In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study.