Rationale for estrogen with interrupted progestin as a new low-dose hormonal replacement therapy

This review outlines the basic principles of a novel interrupted progestin hormone replacement therapy (HRT) regimen in which estrogen is given continuously but the progestin is administered in a 3-days-on and 3-days-off schedule. The rationale for this regimen is to prevent receptor down-regulation and allow estrogen to increase estrogen and progestin sensitivity during the progestin-free periods.

The reasons for poor patient acceptance of HRT are reviewed. The association of HRT with breast and endometrial cancer is discussed, as are the potential benefits of HRT on the skeleton and the cardiovascular system. Basic research studies in the rat are described that provide supporting evidence for the interrupted progestin regimen. Clinically, we review a pilot study examining symptom control, bleeding rates, and safety of the interrupted progestin regimen as well as preliminary results of the usefulness of this regimen for add-back therapy in GnRH agonist-treated patients.

Estrogen and progestin receptor measurements in the rat uterus demonstrate a clear up- and down-regulation in response to estrogen and interrupted progestin but not to the continuous administration of estrogen and progestin or estrogen alone. In addition, we found a significant beneficial effect of a low-dose interrupted HRT regimen on bone mineral content and density in an aged rat model of osteopenia, compared with continuous estrogen and progestin or estrogen alone. These results support the hypothesis that the interrupted progestin HRT increases tissue sensitivity to both estrogen and progestin. Clinical studies demonstrated good symptom control, low bleeding rates, endometrial protection, and excellent patient acceptance.

The combination of continuous estrogen with interrupted progestin appears to result in increased sensitivity to estrogen and progestin in estrogen-responsive tissues. As a result, lower doses of estrogen and progestin may be used for HRT with good biological effects. Further clinical studies, preferably in prospective randomized trials, are required to demonstrate reduced bleeding and improved patient acceptance of this new regimen compared to continuous combined HRT.