Apart from its use for the relief of vasomotor symptoms (hot flushes and night sweats), little is known about the effect of hormone replacement therapy (HRT) on signs and symptoms associated with menopause. Studies have been complicated by a high placebo effect and by variations in the types of HRT used. In particular, the relative contributions of estrogen and progestin are difficult to estimate, and progestin is frequently prescribed in different formulations and regimens. Greendale and colleagues assessed the effects of estrogen alone, placebo, and three estrogen-progestin regimens on postmenopausal symptoms in a large multicenter trial.

The study enrolled 875 women from 45 to 64 years of age who had been postmenopausal for one to 10 years and had no major medical contraindications to hormone use. These patients were randomly assigned to receive placebo or conjugated equine estrogen, in a dosage of 0.625 mg daily, alone or as one of three combinations of estrogen and progestin. The progestin combinations included medroxyprogesterone acetate in a dosage of 2.5 mg daily or medroxyprogesterone acetate in a dosage of 10 mg taken 12 days per month, or 200 mg of micronized progesterone taken 12 days per month. All medications were identical in appearance, and the study was double-blinded. Data about demographic variables, medical history, physical activity, use of cigarettes and alcohol, and symptoms were collected at baseline, and symptom information was collected again at 12 and 36 months.

During the three-year study period, 210 women (24 percent) stopped treatment. Approximately one quarter of these withdrawals (51 women) were mandated because of endometrial abnormalities or other medical complications. Eleven women withdrew because of health concerns, and 21 cited “personal reasons.” The remaining 127 women cited various symptoms as the reason for withdrawal, the most common being vaginal bleeding, premenstrual syndrome, vasomotor symptoms, headaches, anxiety/depression and breast tenderness.

When analyzed by original assignment and adherence to therapy, active treatment was statistically superior to placebo in the relief of vasomotor symptoms. The addition of progestin did not appear to change the relief of vasomotor symptoms. Patients receiving progestin did, however, report significantly more breast discomfort than women taking placebo or estrogen alone. Women taking estrogens and those taking progestins reported less weight gain than did those taking placebo. No differences were found between the treatment groups in anxiety, cognitive-affective or musculoskeletal symptoms. When only women who adhered to treatment were considered, benefit was apparent in relief of musculoskeletal symptoms in women taking progestins and, to a lesser extent, in those taking estrogen alone. The effects of HRT on headache and forgetfulness were complicated. Women with headache before the trial reported improvement with estrogen alone compared with placebo or progestin-containing regimens. Conversely, women who did not report headache initially were more likely to develop the symptom during treatment with estrogen than other regimens.

The authors conclude that all forms of HRT benefit vasomotor symptoms but appear to have little effect on anxiety, cognition or affect. They further conclude that the addition of progestin to HRT is associated with breast discomfort.