Ethinyl estradiol and 17ß-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment.

The need to seek improved combined oral contraceptive (COC) efficacy, with fewer health risks and better acceptability, has been ongoing since the introduction of COCs more than 50 years ago. New progestin formulations combined with lower doses of ethinyl estradiol (EE), the predominant estrogenic component of COCs, have reduced the incidence of venous thromboembolism and other negative outcomes of COC treatment. Previous attempts to use endogenous 17ß-estradiol (E2) instead of EE were limited primarily by poor cycle control. The recent introduction of E2-based formulations has renewed interest to determine if there are potential benefits of using E2 in COCs. These formulations have been shown to have similar efficacy and cycle control as EE-based COCs. This review provides a brief summary of the pharmacology of EE and E2, including metabolism, pharmacokinetics and pharmacodynamics, as well as adverse effects of these estrogens.

A stochastic model for transepidermal drug delivery.

BACKGROUND: Topical drug application has been widely used to manage skin diseases as well as to treat a variety of local and systemic disorders. To evaluate the efficiency of transepidermal drug delivery, an efficient model is needed to study the process of percutaneous transport. MODEL DESCRIPTION: A stochastic model based on Monte Carlo methods and Cellular Automata is presented in this work to study the molecular transport through the stratum corneum of the human skin, which is a typical process in transepidermal drug delivery. METHODS: To validate the model, an in vitro experiment on percutaneous absorption of radioactive 17beta-estradiol was performed. RESULTS AND DISCUSSION: The simulation results agree with the experimental data. CONCLUSION: The use and power of the presented approach in studying the process of transepidermal drug delivery were demonstrated.

Parallel assessment of the impact of different hormone replacement therapies on breast density by radiologist- and computer-based analyses of mammograms.

OBJECTIVES: First, to compare the impact of nasally and orally dosed estradiol on breast density; second, to investigate the utility of computer-based automated approaches to the assessment of breast density with reference to traditional methods. METHODS: Digitized images from two 2-year, randomized, placebo-controlled trials formed the basis of the present post hoc analysis. Active treatments were 1 mg estradiol continuously combined with 0.125 mg trimegestone (oral hormone replacement therapy, HRT) or low-dose (150 or 300 microg estradiol) nasal estradiol cyclically combined with 200 mg micronized progesterone (nasal HRT). The effects on breast density were assessed by a radiologist, providing the BI-RADS score and the interactive threshold, and by a computer-based approach, providing the measure of stripiness and the HRT-effect specific measure of breast density. RESULTS: In the oral HRT trial, active treatment induced a significant increase in breast density, which was consistent in all methods used (all p < 0.05). In contrast, none of the methods detected significant changes in women receiving nasal HRT. The sensitivity of automated methods to discriminate HRT- from placebo-treated women was equal or better than the sensitivity of methods performed by the radiologist. CONCLUSIONS: The markedly different pharmacokinetic profile of nasal estrogen seems to be associated with better breast safety. Automated computer-based analysis of digitized mammograms provides a sensitive measure of changes in breast density induced by hormones and could serve as a useful tool in future clinical trials.

Assessment of the estrogenic activity of phytoestrogens isolated from bourbon and beer.

Phytoestrogenic substances have previously been isolated and identified in two alcoholic beverages: bourbon and beer. To delineate the relative potencies of the estrogenic substances of plant origin thus far identified in these commonly consumed alcoholic beverages, we evaluated the ability of biochanin A, beta-sitosterol, genistein, and daidzein to bind to cytosolic estrogen receptor binding sites. The in vitro studies demonstrated that each of the contained substances was capable of effectively competing for cytosolic estrogen receptor binding sites of rat liver and uterus. Further, the two phytoestrogenic constituents of bourbon, beta-sitosterol and biochanin A, were less potent than those present in beer. Given the high concentration of beta-sitosterol in bourbon, we chose to evaluate the estrogenicity of beta-sitosterol in vivo using ovariectomized rats. beta-sitosterol was administered either daily or intermittently at 3 doses, based on amounts previously determined to be present in bourbon. The in vivo studies demonstrated that beta-sitosterol is capable of producing a weak estrogenic effect only at the lowest dose (6.2 micrograms/dl) administered intermittently. These responses suggest that beta-sitosterol may be weakly estrogenic at low doses, but is unable to maintain such an effect at higher doses.