Patient acceptance of standard cyclic hormonal replacement therapy (HRT) has been poor. One major cause of non-acceptance is thought to be the resumption of menses as a result of induced withdrawal bleeding. In order to prevent bleeding, continuous combined estrogen and progestin HRT has been utilized. However, most publications report irregular breakthrough bleeding in a majority of patients receiving the continuous HRT regimen. The cause of the irregular bleeding remains unclear at present. It is known that the continuous presence of progestin causes down-regulation of estrogen and progestin receptors and endometrial atrophy. Endometrial atrophy may result in withdrawal of stromal support for blood vessels leading to dilatation and extravasation of blood. In addition, progestin has been implicated in neovascularization, possibly by stimulation of vascular endothelial growth factor (VEGF). Finally, programmed cell death and apoptosis appear to occur in endometrial stroma after prolonged exposure to progesterone and may contribute to breakthrough bleeding. We have developed a novel interrupted progestin HRT regimen in which estrogen is given continuously, but with progestin administered in a 3-days-on and 3-days-off schedule. The rationale for this regimen is to prevent total receptor down-regulation by allowing estrogen to up-regulate estrogen and progestin receptors during the progestin-free periods. Interrupting the progestin may also prove to be favorable in reducing neo-angiogenesis. Clinically, we have demonstrated low bleeding rates in menopausal women, and in premenopausal women on long-term GnRH-agonist treatment for endometriosis or severe PMS, in whom the interrupted regimen has been used for addback HRT. Further basic and clinical studies, preferably in prospective randomized trials, are required to demonstrate reduced bleeding and improved patient acceptance compared to continuous combined HRT.