2001
Basel, Switzerland
Hormone exposure and effects on Follicle-Stimulating Hormone (FSH) after nasal administration of Estradiol (E2) in postmenopausal women
C. Laveille, C. Christin-Maitre*, C. Varin, Y. Tsouderos, and R. Jochemsen.
Institut de Recherches Internationales Servier, Courbevoie, France. * Endocrinology Department, Saint Antoine Hospital, Paris, France.
Objective: This pharmacokinetic study was designed to characterize the pharmacokinetic (PK) profile of Estradiol (E2) and Estrone (E1), in order to investigate the pharmacokinetic/ pharmacodynamic (PK/PD) relationship between the concentration of E2 and Follicle-Stimulating Hormone (FSH) and to estimate the intra and inter subject variability on the E2 and E1 PK and on the PK/PD parameters, after repeated administration of intranasal 17 b -Estradiol.
Design: 24 healthy female volunteers, menopaused for at least 24 months, received in a cross-over study design , intranasal E2 (300 µg once a day -one puff in each nostril each morning) during two 28 day cycles, without and in combination with an oral progestogen (dydrogesterone 20 mg/day) during the last 14 days of the cycle. Blood samples were drawn on 3 occasions on each of the 2 cycles (Day1, Day14 and Day28) for E2, E1 and FSH measurements.
Results: Absorption of E2 was rapid with maximal plasma concentrations obtained within 10-30 min, then returned to post-menopausal levels within 12 hours leading to a pulsed profile. Ratio E2/E1 was physiologic, about 1, showing the absence of first-pass effect. For E2 exposure, the intra and inter subject variabilities were low and in the same magnitude, about 25 %. Over the dosing interval, FSH levels described a U curve with a minimum around 8 hours after intranasal administration. Furthermore, over the 28-day cycle, FSH pre-dose values decreased: with 18 % between Day1 and Day14 and a further 5 % decrease between Day14 and Day28. A modified physiologic indirect response PK/PD model described these short and mid-term effects, reflecting probably the regulation mechanism of E2 on FSH secretion on one hand and on the biosynthesis of FSH on the other hand. Using a simulation approach, an external model validation was performed on a single phase I and a dose-ranging phase IIb study, respectively.
Conclusion: Intranasal E2 administration leads to a pulsed kinetic profile with high reproducibility of hormonal exposure involving a significant decrease in FSH levels over a dosing interval and over a 28-day cycle.