Activation of nitric oxide synthesis in human endothelial cells using nomegestrol acetate.
OBJECTIVE
Recent clinical trials indicate that synthetic progestins may be unexpectedly relevant for the development of cardiovascular disease. The aim of this study was to establish whether nomegestrol acetate induces signaling events in human endothelial cells that differ from those of other progestins, such as natural progesterone or medroxyprogesterone acetate.


METHODS
We used human endothelial cells to study the action of nomegestrol acetate (either alone or in the presence of estradiol [E2]) on the synthesis of nitric oxide (NO) and on the activity or expression of endothelial nitric oxide synthase (eNOS). We compared the effects of nomegestrol acetate with those of progesterone or medroxyprogesterone acetate. In addition, we characterized the signaling events recruited by these compounds.


RESULTS
Progesterone and nomegestrol acetate increase NO synthesis by transcriptional and nontranscriptional mechanisms, whereas medroxyprogesterone acetate lacks such effects. When used together with physiological E2 concentrations, progesterone and nomegestrol acetate do not interfere with (or even enhance) E2 effects, whereas medroxyprogesterone acetate impairs E2 signaling. A marked difference in the recruitment of mitogen-activated protein kinase and phosphatidylinositol-3 kinase explains the divergent effects of the three gestagens.


CONCLUSIONS
Our findings show significant differences in the signal transduction pathways recruited by progesterone, nomegestrol acetate, and medroxyprogesterone acetate in human endothelial cells that may have relevant clinical implications.
Simoncini
Tommaso
T
Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), 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
Garibaldi
Silvia
S
Fu
Xiao-Dong
XD
Giretti
Maria Silvia
MS
Baldacci
Chiara
C
Scorticati
Camila
C
Fornari
Letizia
L
Mannella
Paolo
P
Genazzani
Andrea Riccardo
AR
D002478:Cells, Cultured; D003271:Contraceptive Agents, Female / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D042783:Endothelial Cells / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology; D008535:Megestrol / Q000494:pharmacology*; D015735:Mifepristone / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000187:drug effects* / Q000378:metabolism; D009649:Norpregnadienes / Q000494:pharmacology*; D011374:Progesterone / Q000494:pharmacology; D045167:Progesterone Congeners / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
D003271:Contraceptive Agents, Female; D009649:Norpregnadienes; D045167:Progesterone Congeners; D009569:Nitric Oxide; D015735:Mifepristone; D011374:Progesterone; D004958:Estradiol; C038501:nomegestrol acetate; D017258:Medroxyprogesterone Acetate; D008535:Megestrol; D019001:Nitric Oxide Synthase