Preovulatory administration of clomiphene citrate to mice causes fetal growth retardation and neural tube defects (exencephaly) by an indirect maternal effect

Abstract

Clomiphene citrate was administered to female mice at different doses and different times prior to ovulation, in the preimplantation period after ovulation, and after implantation. Pregnancy outcome was determined on day 15 of gestation, when the number of implantations and resorptions were calculated relative to the number of ovulations, and fetuses were assessed for size and stage of development and morphological abnormalities. Preovulatory administration of clomiphene citrate caused decreased implantation rates and growth retardation of surviving fetuses, the degree of the effect being dependent on the dose and the time of drug injection relative to ovulation. The implantation rate was lowest, and the degree of fetal growth retardation highest, when clomiphene citrate was administered immediately before ovulation. An increased incidence of exencephaly was found in the fetuses of females injected with clomiphene citrate prior to ovulation. Transfer of blastocysts from treated mice to untreated fosters showed the effect of clomiphene citrate on implantation and fetal growth to be predominantly mediated through the female reproductive tract, rather than a direct effect on the embryo itself. Administration of clomiphene citrate in the preimplantational period resulted in complete inhibition of implantation, while the only effect when administration was after implantation was a slight reduction in fetal weight. These results indicate that preovulatory clomiphene citrate impairs uterine function, which has an indirect effect on the growth and development of the postimplantation embryo.

Clinical use of aromatase inhibitors (AI) in premenopausal women

“…As prefatory comment to this discussion on AIs' safety, it should be remembered however that CC too has been extensively documented to bear teratogenic properties when administered to pregnant animals [21][22][23]. Drawing on the vastly documented embryotoxicity of CC in various animal models, one should single out that it likely is the estrogen deprivation in pregnancy that is embryotoxic irrespective of how estrogen deprivation is achieved.…”

Effects of the aromatase inhibitor letrozole on in utero development in rats

“…It acts by blocking the negative effects of estrogen, thereby stimulating secretion of gonadotropins from the pituitary gland (Messinis, 2005). In experimental studies, clomiphene was found to be teratogenic in mice (Dziadek, 1993), rats (Eneroth et al, 1971), and guinea pigs (Motta and Hutchinson, 1991), but not in monkeys (Courtney and Valerio, 1968). Abnormal developmental outcomes included decreased implantation rates, fetal growth retardation and neural tube defects in mice after exposure to doses similar to those used in humans (Dziadek, 1993), hydramnios, cataracts (Eneroth et al, 1971), genital tract abnormalities in female offspring of rats exposed to doses similar to those used in humans (McCormack and Clark, 1979) and pregnancy loss in guinea pigs at clinically relevant doses (Motta and Hutchinson, 1991).…”

“…The mechanisms and etiological factors involved in clomiphene citrate-induced abnormal development remain incompletely elucidated. Impairment of uterine function (Motta and Hutchinson, 1991;Dziadek, 1993), and direct or indirect luteolysis (Motta and Hutchinson, 1991) have been implicated in clomiphene citrate-associated pregnancy loss. The genital tract abnormalities noted in rats were related to the ability of clomiphene citrate to cause long-term estrogenic stimulation (McCormack and Clark, 1979).…”

Fertility Treatment and Childhood Epilepsy

“…The risk of epilepsy was substantial in the sibling analysis further corroborating that exposure to clomiphene citrate may be responsible for the increased risk of child epilepsy. Periconceptional treatment with clomiphene citrate has been associated with offspring neural tube defects in a previous animal study 29 , although this finding remains controversial in human studies 30,31 . Our study supports the hypothesis that clomiphene citrate may have an impact on the developing central nervous system.…”