Effects of dydrogesterone and of its stable metabolite, 20-alpha-dihydrodydrogesterone, on nitric oxide synthesis in human endothelial cells.
OBJECTIVE
To investigate the effects of P, medroxyprogesterone acetate (MPA), and dydrogesterone (DYD) and its metabolite, 20-alpha-dihydrodydrogesterone (DHD) on endothelial synthesis of nitric oxide (NO) and characterize the signaling events recruited by these compounds. The Women's Health Initiative trial reports an excess of heart disease in postmenopausal women receiving MPA.


METHODS
Cell culture.


METHODS
Research laboratory.


METHODS
Human endothelial cells from umbilical vein.


METHODS
Treatments with P, MPA, DYD, or DHD.


METHODS
Measure of NO release, endothelial nitric oxide synthase (eNOS) activity and expression, and activation of ERK 1/2 and Akt.


RESULTS
The administration of DYD alone or in combination with estrogen to endothelial cells results in neutral effects on NO synthesis and on the activity and expression of eNOS. In parallel, the stable metabolite DHD acts similarly to natural P, enhancing the expression of eNOS and inducing rapid activation of the enzyme through the regulation of the ERK 1/2 mitogen-activated protein kinase cascade. 20-Alpha-dihydrodydrogesterone and P also potentiate eNOS induction by E2. On the contrary, MPA does not trigger eNOS enzymatic activation and decreases the extent of eNOS induction by E2.


CONCLUSIONS
These findings support the concept that synthetic progestins act differently on vascular cells and that hormonal preparations may differ as to their cardiovascular effects.
Simoncini
Tommaso
T
Molecular and Cellular Gynecological Endocrinology Laboratory, Department of Reproductive Medicine and Child Development, Division of Obstetrics and Gynecology, University of Pisa, Pisa, Italy. t.simoncini@obgyn.med.unipi.it
Caruso
Antonella
A
Giretti
Maria Silvia
MS
Scorticati
Camila
C
Fu
Xiao-Dong
XD
Garibaldi
Silvia
S
Baldacci
Chiara
C
Mannella
Paolo
P
Fornari
Letizia
L
Genazzani
Andrea R
AR
D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004394:Dydrogesterone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004958:Estradiol / Q000494:pharmacology; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000235:genetics; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D011374:Progesterone / Q000494:pharmacology; D011372:Progestins / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
C514239:20-alpha-dihydrodydrogesterone; D011372:Progestins; D009569:Nitric Oxide; D011374:Progesterone; D004958:Estradiol; D004394:Dydrogesterone; D017258:Medroxyprogesterone Acetate; D052250:Nitric Oxide Synthase Type III; D020928:Mitogen-Activated Protein Kinases