Combined continuous hormone replacement therapy: a critical review

Abstract

Objective: To evaluate the putative benefits of combined continuous hormone replacement therapy for postmenopausal women.

Data sources: A Medline search was performed for relevant English-language studies published during 1981-1995.

Method of study selection: Forty-two studies were identified, all using a continuous daily regimen of an estrogen and a progestin given to postmenopausal women with intact uteri.

Data extraction and synthesis: Each study was reviewed for the design, number of subjects enrolled, duration of protocol, and type and dosage of medications used. Data were extracted from texts, tables, figures, or personal communications regarding the effects of treatment on patient compliance (ie, drop-out rates), the occurrence of vasomotor symptoms, uterine bleeding patterns, endometrial histology, and lipid and bone density measurements. These data were then arranged in tabular form for the purpose of comparing and identifying trends. The lipid data from six randomized, double-blind studies that compared sequential and combined continuous regimens of conjugated equine estrogen and medroxyprogesterone acetate were further analyzed by meta-analysis. Findings revealed compliance rates of approximately 80% (range 35-100). Vasomotor symptoms improved almost universally. Irregular uterine bleeding was noted to be a common problem in the first 6 months of treatment; thereafter, most studies reported rates of amenorrhea of 75% or greater. In patients undergoing endometrial biopsy, rates of atrophic endometrium were noted to be 90-100%, and rates of endometrial hyperplasia were less than 1%. Adenocarcinoma of the endometrium was documented in two patients with a history of atypical endometrial hyperplasia and bleeding after established amenorrhea. The effects of treatment on lipid levels varied from study to study, but a meta-analysis revealed the combined continuous and sequential regimens to produce a treatment-associated decline in total and low-density lipoprotein cholesterol and an increase in high-density lipoprotein cholesterol. Studies examining bone density documented either no change or an increase with treatment.

Conclusion: Combined continuous hormone replacement is well accepted by patients in clinical trials, effective in relieving vasomotor symptoms, and produces amenorrhea (though often after an initial period of irregular bleeding), an atrophic endometrium, and favorable changes in circulating lipids as well as maintaining bone density. Data on the impact of this regimen on long-term patient compliance, cardiovascular disease risk, and urogenital atrophy are lacking.