Pharmacodynamic effects of the fetal estrogen estetrol in postmenopausal women: results from a multiple-rising-dose study.
Estetrol (E4) is an estrogen produced exclusively by the human fetal liver during pregnancy. In this study the pharmacodynamic effects of escalating doses of E4 in postmenopausal women were investigated.



This was a partly randomized, open-label, multiple-rising-dose study in 49 postmenopausal women. Participants were randomized to receive either 2 mg E4 or 2 mg estradiol-valerate (E2 V) for 28 days. Subsequent dose-escalation groups were (non-randomized): 10, 20 and 40 mg E4. Blood samples were collected regularly for measuring endocrine and hemostasis variables, lipids and lipoproteins, fasting glucose and bone turnover markers.



Estetrol treatment resulted in a decrease of follicle-stimulating hormone and luteinizing hormone and an increase of sex-hormone binding globulin. Changes in hemostasis variables were small. A lowering effect on low-density lipoprotein cholesterol was accompanied with an increase in high-density lipoprotein cholesterol and no or minimal changes in triglycerides. The considerable decrease in osteocalcin levels in the three highest E4 dose groups and the small decrease in C-telopeptide levels were comparable to the E2 V control group and suggest a preventive effect on bone loss. All changes observed were dose-dependent.



In this study, estetrol treatment showed dose-dependent estrogenic effects on endocrine parameters, bone turnover markers, and lipids and lipoproteins. The effect on triglycerides was small as were the effects on hemostatic variables. These results support the further investigation of estetrol as a candidate for hormone therapy. Quantitatively, the effects of 10 mg estetrol were similar to the study comparator 2 mg estradiol valerate.
1Pantarhei Bioscience BV, Zeist, The Netherlands 2University of Liège, Liège, Belgium 3Department of Women's and Children's Health, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
Herjan J T
HJT
Coelingh Bennink
Carole
C
Verhoeven
Yvette
Y
Zimmerman
Monique
M
Visser
Jean-Michel
JM
Foidart
Kristina
K
Gemzell-Danielsson
D000368:Aged; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D024042:Collagen Type I / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004953:Estetrol / Q000008:administration & dosage* / Q000494:pharmacology*; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood; D008875:Middle Aged; D015675:Osteocalcin / Q000097:blood; D015663:Osteoporosis, Postmenopausal / Q000517:prevention & control; D010455:Peptides / Q000097:blood; D017698:Postmenopause / Q000187:drug effects*; D012738:Sex Hormone-Binding Globulin / Q000032:analysis
D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D024042:Collagen Type I; D010455:Peptides; D012738:Sex Hormone-Binding Globulin; C052929:collagen type I trimeric cross-linked peptide; D015675:Osteocalcin; D004958:Estradiol; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D002784:Cholesterol; D004953:Estetrol