Hormone Replacement Therapy (HRT)

Osteoporosis is one of the long-term consequences of estrogen deficiency. Estrogen deprivation at menopause has been described as the single most important bone loss event in the life of a woman. At least 15 percent of the average female skeleton is lost during the first six or seven years after menopause. Large randomized trials examining the effect of HRT on fractures have not been conducted to date, primarily because estrogen received approval from the US-FDA for osteoporosis without such trials. However, epidemiological studies of HRT have indicated a 50% to 80% decrease in vertebral fractures and a 25% decrease in nonvertebral fractures with 5 years of use.³⁷

The Women’s Health Initiative, a large prospective, randomized trial, placebo-controlled trial in postmenopausal women was expected to go till 2007, instead the combination arm was prematurely halted in summer of 2002 because risks outweighed the benefits. The estrogen only arm of the trial is still continuing. Here are some pivotal references detailing outcome analyses from the trial:

• Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002 Jul 17;288(3):321-33.

• Effects of estrogen plus progestin on health-related quality of life.
N Engl J Med. 2003 May 8;348(19):1839-54.

• Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative randomized trial.
JAMA. 2003 Oct 1;290(13):1739-48.

• Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial. JAMA. 2003 Oct 1;290(13):1729-38.

• Estrogen plus progestin and the risk of coronary heart disease.
N Engl J Med. 2003 Aug 7;349(6):523-34.

• Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial. JAMA. 2003 May 28;289(20):2673-84.

• Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003 May 28;289(20):2651-62.

There has been one small randomized trial showing that transdermal estrogen reduces vertebral fracture rates in 75 postmenopausal women aged 47 to 75 years.³⁸ The results of this study demonstrated a protective effect of transdermal estrogen on vertebral fractures at 1 year. Women receiving active treatment had a 61% reduction in the risk of new vertebral fractures (P=.04) compared to placebo.

EFFECT OF CURRENT ESTROGEN USE ON FRACTURE RISK IN POSTMENOPAUSAL OSTEOPOROTIC WOMEN:12 MONTH STUDY (Patients With at Least One Baseline Vertebral Fracture)

adapted from: Lufkin EG et al. Ann Intern Med. 1992;117:1-9.

Based on these studies, estrogen therapy is indicated for both prevention and treatment of osteoporosis in postmenopausal women. Apparently, the effect of estrogen continues for as long as therapy is continued. Women beginning therapy years after menopause still benefit from therapy, exhibiting positive changes in bone mass.

HRT Controversies:

Better to Wait?

This graph illustrates the theoretical changes in bone density among continuous, never, and late users of ERT, as suggested by Black.³⁹ Initiation of estrogen in late postmenopausal women may actually increase bone mass by about 3 to 10 percent, thus initiation of ERT at a later age may result in only a slightly lower bone mass than if begun at age 50. The Rancho Bernardo Study published results consistent with this data showing that women in their late 70's who began estrogen therapy after age 60 years had a bone density similar to women who had started therapy at menopause. ⁴⁰

Finally, bone density screening at age 65 or 70 probably predicts patients at risk of osteoporosis more reliably than screening at age 50.³⁹ Therefore, screening of older women could help those individuals who stand to gain the most from ERT (in terms of bone protection), while minimizing hormone exposure to those who are not as likely to benefit. As has been stated, since later use of HRT may be associated with a small increase in bone density, as opposed to merely delaying its loss, initiation of ERT at a later age may result in only a slightly lower bone mass than if begun at age 50.

One recent prospective cohort study determined the relationship between estrogen replacement therapy and fractures.⁴¹ In this study of women older than 65 years, current estrogen users were less likely to experience non-spinal fractures (RR, 0.66; 95% CI, 0.54-0.80). The lower rate of hip fracture (RR, 0.6; 95% CI, 0.36-1.02) was not quite significant for the whole group of estrogen users; however, hip fracture was significantly less common (RR, 0.29; 95% CI, 0.09-0.92) for early users, who were defined as women who started estrogen within 5 years of menopause. The authors concluded that current use of estrogen appears to decrease the risk for fracture in older women. These results suggest that for protection against fractures, estrogen should be initiated soon after menopause and continued indefinitely.

Side-Effects

Breast Cancer Risk

The association between breast cancer and postmenopausal hormone replacement therapy is controversial. Many early studies did not find an increased risk for breast cancer among women who had taken ERT, while more recent studies have shown an association between use of postmenopausal ERT/HRT and the development of breast cancer.⁴² of 30 to 50 percent. This change is thought to reflect the fact that hormonal therapy is now more commonly prescribed for a longer period than was used for earlier studies.

The United States Breast Cancer Detection demonstration Project (BCDDP), which analyzed data from over 280,000 women, showed a relationship between duration of use and breast cancer. The relative risk for breast cancer was 1.5 for greater than 20 years of use of ERT/HRT. The risk for breast cancer may be slightly higher among women using HRT (compared to ERT). Two prospective studies found a 60 to 70 percent increased risk associated with 5 to 10 years of use of HRT.⁴³There was also a trend shown for an increase in risk with increase in length of exposure. Unfortunately, the available studies have been observational in design, and are subjected to bias.

Endometrial Cancer Risk

Endometrial cancer is the third most common cancer in women in the United States. Unopposed estrogen therapy substantially increases the risk of endometrial cancer. Of women with an intact uterus who receive ERT, approximately 12 to 40 percent will develop endometrial hyperplasia (the percentage increases with increasing length of therapy). Between 3 and 75 percent of women who develop endometrial hyperplasia go on to develop endometrial cancer; the risk depends upon length of follow-up and severity of hyperplasia at time of diagnosis.⁴⁴ Fortunately, the addition of a progestin reduces the risk of endometrial cancer to that of women not taking hormones.

• Nausea - take with food, gradually increase to maintenance dose, or switch to transdermal route of administration
• Breast tenderness - reduce estrogen dose, switch to different progestin, limit caffeine, add diuretic
• Bloating - switch to different progestin, lower progestin dose, or add intermittent diuretic
• Vasomotor symptoms - increase estrogen dose, switch to transdermal route of administration of estrogen
• Heavy withdrawal bleeding - decrease estrogen dose, switch to continuous dosing regimen, or switch to a 19-nortestosterone progestin (norethindrone)

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