RATIONALE FOR ESTROGEN WITH INTERRUPTED PROGESTIN AS A NEW LOW-DOSE HORMONAL REPLACEMENT THERAPY

OBJECTIVE: This review outlines the basic principles of a novel interr upted progestin hormone replacement therapy (HRT) regimen in which est rogen is given continuously but the progestin is administered in a 3-d ays-on and 3-days-off schedule. The rationale for this regimen is to p revent receptor down-regulation and allow estrogen to increase estroge n and progestin sensitivity during the progestin-free periods. METHODS : The reasons for poor patient acceptance of HRT are reviewed. The ass ociation of HRT with breast and endometrial cancer is discussed, as ar e the potential benefits of HRT on the skeleton and the cardiovascular system. Basic research studies in the vat are described that provide supporting evidence for the interrupted progestin regimen. Clinically, we review a pilot study examining symptom control, bleeding rates, an d safety of the interrupted progestin regimen as well as preliminary r esults of the usefulness of this regimen for add-back therapy in GnRH agonist-treated patients. RESULTS: Estrogen and progestin receptor mea surements in the rat uterus demonstrate a clear up- and down-regulatio n in response to estrogen and interrupted progestin but not to the con tinuous administration of estrogen and progestin or estrogen alone. In addition, we found a significant beneficial effect of a low-dose inte rrupted 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 inter rupted progestin HRT increases tissue sensitivity to both estrogen and progestin. Clinical studies demonstrated good symptom control, low bl eeding rates, endometrial protection, and excellent patient acceptance . CONCLUSION: The combination of continuous estrogen with interrupted progestin appears to result in increased sensitivity to estrogen and p rogestin in estrogen-responsive tissues. As a result, lower doses of e strogen and progestin may be used for HRT with good biological effects . Further clinical studies, preferably in prospective randomized trial s, ave required to demonstrate reduced bleeding and improved patient a cceptance of this new regimen compared to continuous combined HRT.