Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism

Data on the specific effects and bioequivalency of the different forms of estrogen are lacking, and in the young adolescent age group in particular, virtually non-existent. This has been complicated further by the difficulty in accurately interpreting estradiol assay results as the conventional radioimmunoassays (RIA) for estradiol are inaccurate and insensitive measuring very small concentrations in plasma. There is wide variation in the types of estrogens used for estrogen replacement, as well as doses and route of administration. Girls with Turner syndrome (TS) represent an important case study for these issues as they have early primary gonadal insufficiency or failure many years before the achievement of peak bone mass. Hence, a study of the effects of different estrogen compounds in this patient population offers a unique model that eliminates the confounding effects of other products produced by the intact gonad. Since in this condition it is imperative that estrogen replacement is started during the adolescent years and continued for several decades, this issue becomes highly relevant to these young women's health.Our specific aims are to: 1. to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) and relative biological potency of different oral vs. transdermal preparations of estradiol using state-of-the-art tandem mass spectrometry assays and recombinant cell bioassays; 2. to investigate the differential, long term metabolic effects of oral vs. transdermal estrogen replacement, specifically the effects on lipid and protein metabolism as well as body composition in this patient population; 3. to determine feasibility of estrogen concentration-based dosing in puberty and 4. To characterize the metabolic profile of TS girls previously treated with GH. To accomplish this we will study girls/young woman between ages 13 to 20 with TS in 2 protocols. Protocol #1 will be a study of the pharmacokinetic/pharmacodynamic (PK/PD) of 3 different preparations of estrogen in different doses. Protocol #2 will be a one year longitudinal study of the effects of oral vs. transdermal (TD) estrogen on body composition, hormones and growth factors.