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Menopause Matters

Low-Dose ERT/HRT
Evaluating Clinical Efficacy

Wulf H. Utian, MD, PhD

Benefits of estrogen replacement therapy (ERT) and hormone replacement therapy (HRT; estrogen plus a progestogen) for the relief of menopausal symptoms and risk reduction of osteoporosis are well documented. Despite the known and potential advantages of ERT/ HRT, many women are unwilling either to start therapy or to continue it after a few months of use. This reluctance is often due to concerns about safety and side effects, particularly uterine bleeding.¹ Recent studies have shown that ERT/HRT doses that are lower than current standard doses may decrease the incidence of side effects without sacrificing efficacy and safety.

For example, a randomized, double-blind, placebo-controlled, parallel-group study conducted on 196 women with moderate to severe vasomotor symptoms showed that low-dose transdermal estradiol was effective in relieving hot flashes.² After 12 weeks of treatment with transdermal estradiol 0.025, 0.05, or 0.1 mg daily, the frequency of hot flashes decreased significantly in all dose groups when compared with the placebo group. Estrogen-related adverse events, including metrorrhagia and endometrial hyperplasia, were less common in the 0.025-mg group than in the higher-dose groups.

WOMEN'S HOPE STUDY
The Women's HOPE (Health, Osteoporosis, Progestin, Estrogen) Study has provided additional evidence of the efficacy and safety of lower-dose oral ERT/HRT.^3-6 This 2-year prospective, randomized, double-blind, placebo-controlled trial enrolled 2673 postmenopausal, nonhysterectomized women aged 40 to 56. Investigators evaluated eight daily regimens: conjugated equine estrogens (CEE) 0.625 mg (the most commonly prescribed oral ERT regimen), CEE 0.625 mg plus medroxyprogesterone acetate (MPA) 2.5 mg (the most commonly prescribed oral HRT regimen), CEE 0.45 mg, CEE 0.45 mg plus MPA 2.5 mg, CEE 0.45 mg plus MPA 1.5 mg, CEE 0.3 mg, CEE 0.3 mg plus MPA 1.5 mg, and placebo.

Hot Flashes
Within 3 weeks, vasomotor symptoms decreased significantly in both frequency and severity in all active-treatment groups relative to the placebo group.³ No significant between-group differences were observed among HRT recipients. Also, low-dose HRT was as effective as CEE 0.625 mg, suggesting that MPA may have a synergistic effect with CEE.

Vaginal Atrophy
The vaginal maturation index, a measure of vaginal atrophy, was significantly improved in all active-treatment groups relative to baseline and relative to the placebo group.³ Changes were similar in the lower-dose and higher-dose groups. Endometrial Effects

Of 32 cases of endometrial hyperplasia, 29 occurred in women using unopposed CEE 0.625 mg or CEE 0.45 mg.⁴ This finding supports the recommendation that a progestogen be added to estrogen in women with an intact uterus to reduce the risk of endometrial cancer. Overall, lower HRT doses and standard HRT doses provided similar endometrial protection.⁴ However, lower doses were associated with a more favorable uterine bleeding pattern, including higher rates of amenorrhea.⁵

Cardiovascular Effects
Researchers examined the effects of low-dose ERT/HRT on plasma lipids, hemostatic factors, and carbohydrate metabolism.⁶ All active-treatment groups had improvements in high- and low-density lipoprotein cholesterol levels and in coagulation and fibrinolytic parameters, although beneficial lipid changes were not as great in the lower-dose groups as in the standard-dose group. Carbohydrate metabolism and glucose tolerance were minimally affected by low-dose hormone administration. It should be noted that these were 1-year results; an assessment of longer-term use of low-dose ERT/ HRT is warranted.

Effects on Bone
A preliminary assessment of unpublished data indicates that all doses of ERT/HRT preserved bone mineral density (BMD) at the spine and hip after 2 years of treatment. BMD increased significantly relative to baseline in all treatment groups. (An exception was femoral neck BMD in CEE 0.3 mg recipients.) In all active-treatment groups, dose-response effects were observed for spine BMD but not for hip BMD. In contrast to the bone preservation seen in actively treated groups, BMD declined in the placebo group. Side Effects

In general, treatment-associated adverse events were less frequent in the lower-dose groups.

Clinical Implications
Results from this large, well-controlled study indicate that lower-than-standard doses of ERT/HRT are as effective as the most commonly used doses for relieving many menopausal symptoms. Also, low-dose HRT has a more favorable bleeding profile and protects against endometrial hyperplasia.

RECOMMENDATIONS
Based on these data, clinicians should consider prescribing lower ERT/HRT doses for any menopause-related condition that the US Food and Drug Administration has recognized as an indication for hormone therapy. The decision to reduce hormone doses in women now using standard regimens should be individualized. It may be particularly prudent to make such a switch in women older than 65, given their increased sensitivity to endogenous hormones. However, this requires additional study.

CEE 0.3 or 0.45 mg daily (plus MPA 1.5 or 2.5 mg/d in nonhysterectomized women) may be appropriate in many cases, but clinicians are limited to dosage formulations that are on the market. It is expected that, at a minimum, a formulation containing CEE 0.45 mg daily (or its equivalent) plus MPA 1.5 mg daily will become available.

REFERENCES

1. Ettinger B, Pressman A, Silver P. Effect of age on reasons for initiation and discontinuation of hormone replacement therapy. Menopause. 1999;6:282-289.
   
2. Utian WH, Burry KA, Archer DF, et al, for the Esclim Study Group. Efficacy and safety of low, standard, and high dosages of an estradiol transdermal system (Esclim) compared with placebo on vasomotor symptoms in highly symptomatic menopausal patients. Am J Obstet Gynecol. 1999;181:71-79.
   
3. Utian WH, Shoupe D, Bachmann G, et al. Relief of vasomotor symptoms and vaginal atrophy with lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Fertil Steril. 2001;75:1065-1079.
   
4. Pickar JH, Yeh I, Wheeler JE, et al. Endometrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate. Fertil Steril. 2001;76:25-31.
   
5. Archer DF, Dorin M, Lewis V, et al. Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on endometrial bleeding. Fertil Steril. 2001;75:1080-1087.
   
6. Lobo RA, Bush T, Carr BR, Pickar JH. Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on plasma lipids and lipoproteins, coagulation factors, and carbohydrate metabolism. Fertil Steril. 2001;76:13-24.

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