Clinical Review

Postmenopausal HRT: What is fact, what is fiction?

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What the evidence to date does and does not confirm



Now that the dust is settling from the Women’s Health Initiative (WHI), our patients are again asking reasonable questions about hormone replacement therapy (HRT). I remind them of estrogen’s proven advantages in menopause, as well as its risks. Although most women are generally aware of these risks and benefits, considerable misunderstanding persists. This article reviews what the evidence to date does and does not confirm, particularly regarding breast cancer and coronary heart disease, where most of the uncertainty remains.

HRT stops vaginal atrophy, hot flashes, and bone loss

Three applications form the basis for HRT in postmenopausal women:

  1. Hot flashes subside. Hot flashes occur with varying intensity in about 85% of women, and are effectively treated with estrogen, whether given orally, transdermally, or vaginally.1,2 As long as an appropriate blood level of the hormone is reached, hot flashes diminish.3-5 This reduction is dose-related.
  2. Measurable improvements in vaginal atrophy. Estrogen’s efficacy in relieving dryness, itching, burning, and dyspareunia is well demonstrated, regardless of the route of administration.3,6,7 A fall in vaginal pH from 6.0 to 5.0 after estrogen administration has been documented,8 as has the increase in the number of superficial cells of the vagina with exogenous estrogen.9
  3. HRT maintains or increases bone mineral density (BMD). Most estrogen preparations on the US market have been shown to improve BMD.10-15 “Improvement” means no significant loss, or an increase, in BMD. In the WHI, both vertebral and nonvertebral fractures diminished unequivocally in women using estrogen—alone or with a progestin.16,17 Other clinical trials also have shown increased BMD, as well as decreased urinary and serum markers of bone turnover.

Do new data link progestin to cancer?

Although compelling evidence supports the use of progestational agents in addition to estrogen to prevent endometrial hyperplasia and endometrial cancer,18 a 2005 report19 suggests that chronic, long-term use of estrogen with a progestin may increase the risk of endometrial carcinoma. Because this is the only study in which this risk has been found, corroboration is required.

Until then, give progestin at a sufficient dose and duration to inhibit endometrial hyperplasia.20-25

Effects on heart disease may be age-related

With notable exceptions, the overall conclusion of clinical trials and observational studies to date is that estrogen helps prevent coronary heart disease (CHD).26-30 This finding was first observed in the late 1980s with evidence that estrogen increases high-density lipoprotein (HDL) cholesterol and reduces total and low-density lipoprotein (LDL) cholesterol.31

Some experts argue that these observational trials are biased because many of the women taking estrogen had modified their lifestyles to maintain their weight, control their diet, and exercise regularly.32 Indeed, the randomized, placebo-controlled Heart and Estrogen Replacement Study (HERS) and both arms of the WHI trial found no evidence for a significant increase or decrease in CHD events.33-35

Time from menopause to HRT may be key

Both the HERS and WHI trials enrolled older women who had entered menopause a few months to several years before starting HRT.36 In addition, the estrogen-progestin arm of the WHI trial lacked sufficient power to detect a significant difference in CHD outcomes.37

The WHI findings contrast those of the large, ongoing, observational Nurses Health Study, which has shown a consistent decrease in CHD incidence in women who began HRT with the onset of menopausal symptoms.27-30 The most recent data suggest that the interval between menopause and the start of HRT may explain the different findings in randomized, controlled trials and observational studies.38 The WHI data support this theory: CHD was lower in women who began taking HRT within 5 years of menopause, compared with women who initiated HRT more than 5 years afterward.36 In addition, data from the estrogen-only arm of the WHI show fewer CHD events in women younger than 60.34

Several other studies support this hypothesis:

  • The surgically postmenopausal cynomolgus macaque had a lower rate of atherosclerotic plaque development when estrogen was given, with or without a progestin.39,40
  • In the Rancho Bernardo study, women who had used HRT had less cardiac calcification documented by computed tomography, compared with nonusers.41
  • Estrogen has been shown, by measurement of carotid intimal medial thickness, to inhibit atherosclerotic plaque in humans.42
  • Older women with established atherosclerosis do not undergo any significant change in plaque size with the use of exogenous estrogen.43

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