Pharmacokinetics and pharmacodynamics of oral and transdermal 17β estradiol in girls with Turner syndrome

Abstract

Context: The type, dose, and route of 17β-estradiol (E(2)) used to feminize girls with Turner syndrome (TS) is not well established.

Objective: The objective of the study was to characterize pharmacokinetics and pharmacodynamics of oral vs. transdermal E(2).

Setting: The study was conducted at a clinical research center.

Subjects: Ten girls with TS, mean age 17.7 ± 0.4 (se) yr and 20 normally menstruating controls (aged 16.8 ± 0.4 yr) participated in the study.

Interventions: TS subjects were randomized 2 wk each to: low-dose daily oral (0.5 mg) and biweekly transdermal E(2) (0.0375 mg) with 2 wk washout in between or high-dose oral (2.0 mg) and transdermal (0.075 mg), studied for 24 h each. Tandem mass spectrometry E(2) and estrone (E(1)) assays and a recombinant cell bioassay were used.

Results: Controls consisted of the following: E(2), 96 ± 11 pg/ml (se), E(1), 70 ± 7 (mean follicular/luteal). TS consisted of the following: E(2), average concentration on low-dose oral, 18 ± 2.1 pg/ml, low-dose transdermal, 38 ± 13, high-dose oral, 46 ± 15, high-dose transdermal, 114 ± 31 pg/ml. E(1) concentrations were much higher on oral E(2) (low or high dose) than transdermal in TS and higher than controls. Bioestrogen was closest to normal in the high-dose transdermal group. LH and FSH decreased more in transdermal than oral low-dose routes and similarly in the high-dose oral and transdermal groups. IGF-I concentrations were variable (P = NS) among groups, and low-density lipoprotein/high-density lipoprotein cholesterol responses were variable.

Conclusions: Transdermal E(2) results in E(2), E(1), and bioestrogen concentrations closer to normal and achieves greater suppression of LH/FSH in lower doses compared with normal. Whether the long-term metabolic effects of estrogen differ using the same form of E(2), depending on route, awaits further study in TS.

Figures

Fig. 1.

E2 plasma concentration over time in the top panel (A) and E1 concentrations in the lower panel (B) after PO vs. TD estradiol in low (LD) and high-doses (HD). The highest E2 concentration was observed after high-dose (0.075 mg) TD E2 approximately 12 h after administration. E1 concentrations were much higher after oral E2 than TD. Bars on the left represent estradiol or E1 concentrations in healthy age-matched controls averaged from follicular and luteal phase values. Double bar on the x-axis indicates the 2 wk gap between baseline and the clinical research center admission 2 wk after dosing.

Fig. 2.

Average E2, E1, and bioestrogen concentrations (C-average) in girls with Turner syndrome treated with low-dose (LD) oral (0.5 mg) and transdermal (0.0375 mg) E2 or high-dose (HD) oral (2.0 mg) or transdermal (0.075 mg) E2. Concentrations of the same types of estrogen from a group of age-matched normally menstruating controls were shown for comparison (data represent mean of follicular and luteal phase concentrations).

Fig. 3.

Pharmacodynamics of E2 administration on LH (A), FSH (B), and IGF-I concentrations (C) measured over 24 h, 2 wk after initiation of treatment. Pairwise comparisons of the changes in LH between the different groups showed significantly greater reductions in LH in the TD vs. oral route in both low (P = 0.028) but not the high-dose (P = 0.28) estradiol administration. Similar comparisons of changes in FSH between the different groups showed significantly greater reductions in FSH in the TD vs. oral route only in the low-dose group (P = 0.009), with similar reductions in the high-dose oral and TD groups (P > 0.99). IGF-1 concentrations did not change significantly in any of the groups.