Women are conflicted about hormone therapy. Many suffer the early symptoms of menopause such as hot flashes and vaginal dryness and worry about bone loss that might lead to osteoporosis; yet they’re reluctant to begin hormone replacement therapy (HRT) because of unwanted side effects and a fear that HRT will increase their risk of breast cancer.

Results of recently conducted controlled trials show that lower doses of HRT may offer women many of the same benefits of the standard higher-dose formulations but without as many undesirable side effects. For many women this new option may make HRT a choice they can live with.

The promise and perils of HRT have long created uncertainty for many women. As well as effectively relieving the immediate symptoms of menopause such as the hot flashes and tissue changes, HRT preserves bone density, lowering the risk for osteoporosis. It was also believed to lower a woman’s risk for heart disease and stroke, but this issue has become muddied in recent years. Several large studies show that HRT actually increases the risk of heart attack and stroke, at least in the first two years of use, although it may have heart benefits for those who take it longer.

Perhaps the most daunting issue for women is the fact that, when used for five years or more, HRT appears to increase a woman’s risk for developing breast cancer. Estrogen also increases the risk of endometrial cancer, so women with an intact uterus must add progestin to estrogen to counter that risk.

Uncertainty about HRT is reflected in poor compliance with therapy. Many women who are prescribed HRT either fail to have their prescription filled or discontinue use within a year. Most women who stop using HRT do so because of unacceptable side effects such as breast tenderness, headaches and vaginal bleeding. Breakthrough bleeding was cited in one study as the main reason women have for discontinuing HRT.

Finding Lowest, Effective Dose
In an effort to address these concerns researchers are trying to determine the lowest dose of HRT that will minimize breakthrough bleeding and breast tenderness while still controlling menopausal symptoms. The effect of any regimen on long-term health concerns such as heart disease, stroke, mental status and osteoporosis are also key concerns.

A two-year, placebo controlled trial known as the Women’s HOPE ( Health, Osteoporosis, Progestin, Estrogen) study enrolled 2,673 healthy postmenopausal women between the ages of 40 and 65. The women were divided into eight groups. Some were given the standard dose of .625 milligrams of conjugated equine estrogen (CEE), sold under the brand name Premarin. Other groups received doses of .425 milligrams of Premarin or .3 milligrams of Premarin. Some of the women in these groups were also prescribed progestin (medroxyprogesterone acetate - MPA) and some were not. Another group of women received placebo pills.

At the end of a year the women taking the lower doses of estrogen showed no difference in severity of menopausal symptoms such as hot flashes and vaginal thinning and dryness when compared with women taking the standard dose. Lower doses of HRT also caused less bleeding and provided a comparable level of protection to the endometrium.

A subgroup of 822 women were evaluated for bone mineral density, an indication of how well lower doses of HRT might protect against osteoporosis. All groups taking hormones saw increases in bone mineral density at the spine. All the women taking hormones also saw an increase in bone mineral density at the hip, except those taking the .3 mg dose of estrogen.

The importance of HRT for preserving bone mass was underlined by the fact that in the HOPE study the placebo group lost significant amounts of bone mineral density at all sites measured compared with their baseline levels. This loss occurred despite the fact that all women in the study were given 600 mg of calcium from a supplement. This suggests that increasing calcium intake after menopause is not enough to prevent bone loss.

Another issue addressed by the HOPE study of interest to both women and their doctors is whether lower doses of estrogen are effective when combined with lower doses of progesterone. The study showed that both the lower doses of estrogen (0.45 and 0.3 mg per day) increased bone mineral density when used with either the standard dose of progesterone (2.5 mg of MPA per day) or with a lower dose (1.5 mg of MPA per day).

These findings are consistent with those of a number of smaller studies evaluating the effectiveness of lower-dose hormones on postmenopausal bone loss, including one study of older women treated with low dose HRT plus vitamin D and calcium supplements. The older women showed an increase in bone mineral density with few adverse side effects.

To date studies of low-dose HRT have been able to demonstrate the effectiveness of lower doses in treating hot flashes and vaginal dryness with fewer unpleasant side effects than higher-dose formulations. Low-dose therapy also appears to be effective in preventing bone loss.

Other questions remain unanswered, however. Some studies suggest that lower-dose HRT is less likely to increase the risk of heart attack and stroke. In the HOPE study all women taking HRT showed an improvement in blood lipids with higher levels of HDL (the “good” cholesterol) and lower levels of LDL (the “bad” cholesterol). Triglycerides, another risk factor for heart disease, rose in all those taking hormones, although more in those taking the standard dose compared with those on low-dose therapy. Fibrinogen levels, also a risk factor for heart disease, improved in all HRT groups. Whether this translates into fewer heart related deaths among healthy women remains to be seen.

The issue of breast cancer risk remains unresolved. Although it makes sense to think that lower doses of HRT will mitigate negative effects on breast tissue, there is still no evidence to support this.

More definite answers on the relationship between HRT and breast cancer may come when the results of the Women’s Health Initiative (WHI) become available in 2005. WHI is a national trial that has enrolled thousands of women from all socioeconomic levels and ethnic groups in the United States in an effort to evaluate the risks and benefits of HRT, especially with relation to heart disease, osteoporosis and the risk of cancer.

For now, results from the Women’s HOPE study show that low-dose hormone therapy is both safe and effective. At lower doses HRT is able to offer women many of the benefits of HRT while minimizing at least some of the undesirable side effects.

REFERENCES
“By the Way, Doctor–Can I Take a Lower Dose of HRT?” Harvard Women’s Health Watch, September 2001.
Stacy Diloreto and Rosie Roantree, “An Alternative to Standard HRT Regimens,” Patient Care, October 15, 2001.
Nan Kathryn Fuchs, “Understanding Estrogen,” Women’s Health Letter, March 2002.
“Has Lower–Dose HRT Come of Age?” Women’s Health Watch, June 2002.
“Hormone Therapy May Be Most Protective in Women with Healthiest Blood Vessels,” Women’s Health Weekly, April 11, 2002.
“Hot Flash! More from the HERS Trial,” Internal Medicine Alert, March 29, 2002.
Kate Johnson, “Low-Dose Estrogen Linked to Lower Heart Disease Risk,” Ob Gyn News, February 1, 2001.
Robert Lindsay et al, “Effect of Lower Doses of Conjugated Equine Estrogens with and without Medroxyprogesterone Acetate on Bone in Early Postmenopausal Women,” JAMA, May 22, 2002.
Mary Ann Moon, “Low-Dose HRT Cuts Hot Flashes, Helps Bones,” Family Practice News, September 1, 2001.
Maryann Napoli., “Postmenopausal Hormone Therapy: an Update,” HealthFacts, March 2002.
“Research Gives Nod to Lower-Dose HRT,” Contraceptive Technology Update, August 2001
Richard Sadovsky, “Effect of Low-Dose Hormone Replacement Therapy on Bone,” American Family Physician, January 15, 2000..
BrianVastag, “Hormone Replacement Therapy Falls Out of Favor with Expert Committee,” JAMA, April 17, 2002.
Anne Walling, “Does HRT Increase the Risk of Breast Cancer?” American Family Physician, March 1, 2002.