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Pharmacodynamics of Follicle Stimulating Hormone (FSH) in Postmenopausal Women during Pulsed Estrogen Therapy: Evidence That FSH Release and Synthesis Are Controlled by Distinct Pathways

Endocrinology Department, EA 1533 Paris VI University, Saint-Antoine Hospital (S.C.-M.), 75012 Paris, France; Institut de Recherches Internationales Servier (C.L.), 92415 Courbevoie Cedex, France; Clinical Biology Department (J.C.) and Bone and Cartilage Metabolism Unit (J.-Y.R.), Centre Hospitalier Universitaire, University of Liège, B-4000 Liège, Belgium; and Versus, Clinical Pharmacology Unit (N.B.), 92300 Levallois-Perret, France

Address all correspondence and requests for reprints to: Dr. S. Christin-Maitre, Service d’Endocrinologie, Hôpital Saint-Antoine, 184 rue du Faubourg, St. Antoine, 75012 Paris, France. E-mail: sophie. christin-maitre{at}sat.ap-hop-paris.fr.

17ß-Estradiol (E2) exerts negative feedback effects at the hypothalamo-pituitary level on serum FSH. This study investigated the effects of repeated daily administration of intranasal E2 (S21400) on the pharmacokinetics (PK) of E2 and estrone (E1) and the pharmacodynamics (PD) of FSH and assessed the PK/PD relationship between E2 and FSH using population model-dependent analysis. Postmenopausal volunteers (n = 24) received according to a balanced cross-over design, two 28-d treatments separated by a 2-month wash-out period: 300 µg E2, either alone or combined with oral dydrogesterone (20 mg/d) during the last 14 d of one of the treatments. Absorption of E2 was rapid, with maximal plasma concentrations at 10–30 min, returning to postmenopausal levels within 12 h. Over the 24-h period, FSH levels showed a U curve, with a minimum around 8 h after E2 administration. Moreover, over the treatment period, FSH basal values decreased by 17% between d 1 and 14 and an additional 5% between d 14 and 28. A PK/PD model described these short- and mid-term effects, possibly reflecting separate regulation mechanisms by E2 on FSH release and biosynthesis, respectively. The administration of progestin had no influence on E1, E2, and FSH model parameters. This study suggests that daily transient tissue exposure to E2 after pulsed estrogen therapy elicits short- and mid-term effects on the gonadotropin axis.

Abbreviations: E1, Estrone; E2, 17ß-estradiol; h, human; PD, pharmacodynamics; PK, pharmacokinetics.

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				C. A. Blake, L. M. Brown, M. W. Duncan, S. W. Hunsucker, and S. M. Helmke Estrogen Regulation of the Rat Anterior Pituitary Gland Proteome Experimental Biology and Medicine, December 1, 2005; 230(11): 800 - 807. [Abstract] [Full Text] [PDF]