Failure to achieve a uniform response to estrogen replacement therapy may be related to the dose or route of administration of estrogen. The established doctrines of estrogen replacement therapy are under scrutiny. Recent discoveries have prompted a complete re-evaluation of estrogen action at the biochemical, physiological, and molecular level. Further questions remain as regards the correct dose of estrogen. It is becoming clear that individual cell types respond differently to different doses of estrogen and, even within a single experimental system, a considerable variation in response can be seen. Furthermore, there is an evident link between the duration of exposure to estradiol (continuous versus pulsed) and cellular behavior. In addition to this, it appears that ligand binding has a significant effect on estrogen receptor dynamics. The concept of pulsed estrogen therapy has recently been exploited by the introduction of a nasal spray delivery system. The administration of estradiol via the nasal mucosa is made possible by the use of randomly methylated alpha-cyclodextrin (RAMEB), a beta-cyclodextrin which increases the solubility of estradiol. The original pulsed plasma concentration time profile of E2 following transnasal administration was studied and the results were compared with orally or transdermally administered E2. Being dose-proportional, estradiol transnasally administered at a dose of 300 microg gave an estimated 24-h systemic exposure to exogenous estradiol (area under the curve) close to that of reference treatments. It would appear that pulsed estrogen therapy has a different cellular mechanism to that of traditional forms of administration. This new concept provides reliable dose-dependent exposure to estradiol, avoids the hepatic first-pass effect and demonstrates good biological and clinical efficacy. This development, linked to our improved understanding of the cellular effects of estrogen, ushers in a new era in postmenopausal hormone replacement therapy.