The synthetic progestin, gestodene, affects functional biomarkers in neonatal rat osteoblasts through an estrogen receptor-related mechanism of action.
BACKGROUND
Clinical studies have shown that gestodene (GDN), a potent third-generation synthetic progestin, affects bone resorption. However, its mode of action in bone cells is not fully understood. The aim of this study was to establish whether GDN affects bone directly or through its bioconversion to other metabolites with different biological activities.


METHODS
In this study, we investigated the effects of GDN and its A-ring reduced metabolites on proliferation, differentiation, and mineralization of calvarial osteoblasts isolated from neonatal rat and their capacity to displace [3H]-E2at ER binding sites.


RESULTS
In contrast to progesterone, gestodene did exert significant effects on osteoblast activities. The most striking finding was the observation that the A-ring reduced derivatives 3β,5α-tetrahydro-GDN and 3α,5α-tetrahydro-GDN, though to a lesser extent, had greater stimulatory effects on the osteoblast activity than those observed with GDN. The effects on osteoblast proliferation and differentiation induced by GDN-reduced derivatives were abolished by the antiestrogen ICI 182780, consistent with their binding affinities for the estrogen receptor. In addition, the presence of a 5α-reductase inhibitor or inhibitors of aldo-keto hydroxysteroid dehydrogenases abolished the GDN-induced enhancement of osteoblast differentiation. These results indicated that GDN is metabolized to the A-ring reduced metabolites with estrogen-like activities and through this mechanism, GDN may affect the osteoblast activity.


CONCLUSIONS
Together, the data suggest that synthetic progestins derived from 19-nortestosterone such as GDN, have beneficial effects on bone due to their biotransformation into metabolites with intrinsic estrogenic activity.
a Departamento de Biología de la Reproducción Carlos Gual Castro , Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ) , Ciudad de México , México.
Juana
J
Enríquez
b Departamento de Química Orgánica , Universidad Nacional Autónoma de México (UNAM) , Ciudad de México , México.
Gustavo
G
García
c Departamento de Nefrología y Metabolismo Mineral , INCMNSZ , Ciudad de México , México.
Bertha
B
Herrero
a Departamento de Biología de la Reproducción Carlos Gual Castro , Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ) , Ciudad de México , México.
Fernando
F
Larrea
D058891:5-alpha Reductase Inhibitors / Q000494:pharmacology; D000074408:Aldo-Keto Reductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001667:Binding, Competitive / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D001711:Biotransformation; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D004967:Estrogens / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D009652:Norpregnenes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D011372:Progestins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D017208:Rats, Wistar; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D012886:Skull / Q000166:cytology; D013237:Stereoisomerism
D058891:5-alpha Reductase Inhibitors; D015415:Biomarkers; D004791:Enzyme Inhibitors; D020847:Estrogen Receptor Modulators; D004967:Estrogens; D009652:Norpregnenes; D011372:Progestins; D011960:Receptors, Estrogen; C033273:Gestodene; D000074408:Aldo-Keto Reductases
Synthetic progestins; bone formation; contraceptives; osteoblast differentiation; osteoblast proliferation