Impact of estrogen replacement on letrozole-induced embryopathic effects.
BACKGROUND
The aromatase inhibitor, letrozole, exerts embryo toxic effects in rats, causing increased embryo lethality and anomalies of the axial skeleton at pharmacologically relevant doses. Letrozole acts by inhibiting estrogen biosynthesis. It may thus be feasible that estrogen deprivation is a crucial determinant of the elicited developmental toxic effects. In order to gain insight on this hypothesis, the present study tested the capacity of estrogen replacement in preventing letrozole-mediated embryopathy.


METHODS
Pregnant Sprague Dawley rats were exposed to letrozole alone (0.04 mg/kg), or in combination with estradiol cyclopentylpropionate (ECP) at 0.5, 1 or 2 microg/rat. A control group receiving only the vehicles was also included. Animals were exposed during gestation Days 6-16 (corresponding approximately to 3-10 weeks of gestation in the human). Developmental end-points, including intrauterine mortality, fetal growth, placental weight and incidence of structural abnormalities, were evaluated near term gestation.


RESULTS
Exposure to letrozole alone was lethal for 41% of conceptuses, and caused minor axial skeletal anomalies in 51% of live fetuses. ECP co-administration effectively prevented letrozole-induced embryolethality, but failed to reduce the incidence of axial skeletal alterations.


CONCLUSIONS
The obtained results support the concept that inhibition of estrogen biosynthesis represents a critical determinant of letrozole-induced embryonic mortality. A mechanism other than estrogen deprivation appears to underlie the initiation of skeletal anomalies.
Tiboni
G M
GM
Sezione di Ostetricia e Ginecologia, Dipartimento di Medicina e Scienze dell'Invecchiamento, Facoltà di Medicina e Chirurgia, Università G d'Annunzio, Chieti-Pescara Ospedale SS Annunziata, 66013 Chieti, Italy. tiboni@unich.it
Marotta
F
F
Castigliego
A P
AP
Rossi
C
C
D000014:Abnormalities, Drug-Induced / Q000188:drug therapy / Q000517:prevention & control; D000818:Animals; D047072:Aromatase Inhibitors / Q000633:toxicity*; D004622:Embryo, Mammalian / Q000187:drug effects*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D015914:Estrogen Replacement Therapy; D004967:Estrogens / Q000096:biosynthesis; D005260:Female; D047109:Fetal Development / Q000187:drug effects; D005315:Fetal Diseases / Q000139:chemically induced* / Q000188:drug therapy / Q000517:prevention & control; D000077289:Letrozole; D008297:Male; D018811:Maternal Exposure; D009570:Nitriles / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014230:Triazoles / Q000633:toxicity*
D047072:Aromatase Inhibitors; D004967:Estrogens; D009570:Nitriles; D014230:Triazoles; D004958:Estradiol; C007630:estradiol 17 beta-cypionate; D000077289:Letrozole