Teratogenic and Embryotoxic Effects of Clomiphene Citrate in Developing Mice
1
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
The objective of this study was to assess the teratogenic and embryotoxic effects of clomiphene citrate in mice. The pregnant mice were administered a single dose of clomiphene citrate at different concentrations i.e 1.0, 2.0, 4.0 and 6.0 g/g BW on day 8 of gestation. Fetuses recovered on day 18 of gestation were analyzed on morphological, morphometric and histological basis. Morphological observations showed defects like open eyelids, anophthalmia, fore and hindlimb micromelia, meromelia, amelia, sacral hygroma, hydrocephaly, hemorrhagic spots, kyphosis and clubbed feet. Morphometric analysis indicated a significant (p<0.001) reduction in fetal body weight, crown rump length, head circumference, eye circumference, forelimb and hindlimb lengths and tail size against controls. The histological observations showed brain defects like hydrocephaly, enlarged ventricles and undifferentiated neuroglial cells in cerebellum. Cleft palate, underdeveloped pharynx and atrophy of jaw muscles were the common anatomical defects of pharyngeal region. It is concluded that the concentrations of clomiphene citrate used during the present study proved teratogenic in mice fetuses.
Abstract
The objective of this study was to assess the teratogenic and embryotoxic effects of clomiphene citrate in mice. The pregnant mice were administered a single dose of clomiphene citrate at different concentrations i.e 1.0, 2.0, 4.0 and 6.0 g/g BW on day 8 of gestation. Fetuses recovered on day 18 of gestation were analyzed on morphological, morphometric and histological basis. Morphological observations showed defects like open eyelids, anophthalmia, fore and hindlimb micromelia, meromelia, amelia, sacral hygroma, hydrocephaly, hemorrhagic spots, kyphosis and clubbed feet. Morphometric analysis indicated a significant (p<0.001) reduction in fetal body weight, crown rump length, head circumference, eye circumference, forelimb and hindlimb lengths and tail size against controls. The histological observations showed brain defects like hydrocephaly, enlarged ventricles and undifferentiated neuroglial cells in cerebellum. Cleft palate, underdeveloped pharynx and atrophy of jaw muscles were the common anatomical defects of pharyngeal region. It is concluded that the concentrations of clomiphene citrate used during the present study proved teratogenic in mice fetuses.
참고문헌 (31)
- Adashi, E. Y, "Clomiphene citrate: the case of monoisomeric preparations. Baillieres", Clin. Obstet. Gynaecol, 7, pp.331~347 (1993)
- Aker, H, "Three Neon et al Ca Taract Cases produced in rats with clomiphene citrate", J. Med. Bes, 3(2), pp.185~188 (1985)
- Alatas, C, "Clomiphene citrate and phocomelia", Arch. Genaecol. Obstet, 256(1), pp.33~34 (1995)
- Arriaga-Alba, M, "Assesssment of genetic toxicity of the exposure of clomiphene citrate, with various bacterial test systems", Teratog. Carcing. Mutagen, 21(3), pp.213~221 (2001)
- Asch, R. H, "Update on the safety and efficacy of clomiphene citrate as a therapeutic agent", J. Reprod. Med, 17(3), pp.175~180 (1976)
- Banhidy, F, "Ovarian cysts, clomiphene therapy and the risk of neural tube defects", Int. J. Obstet. Genecol, 100(1), pp.86~88 (2008)
- Bernstein, H. N, "Some tatrogenic ocular diseases from systemically administered drugs", Int. Ophthalmol. Clin, 10, pp.553~618 (1970)
- Brackett, N. L, "Treatment by assisted conception of severe male factor infertility due to spinal cord injury or other neurologic impairment", J. Assist. Reprod. Genet, 12(3), pp.210~216 (1995)
- Casper, R. E, "Aromatase inhibitors in ovarian stimulation", Steriod. Biochem. Mol. Biol, 106(1), pp.71~75 (2007)
- Clark, J. H, "The agonistic-antagonistic properties of clomiphene: a review", Pharmacol. Therapeut, 15, pp.467~519 (1982)
- Csemiczky, G, "Predictive power of clomiphene citrate challenge test for failure of in vitro fertilization treatment", Acta. Obstet. Gynecol. Scand, 81(10), pp.954~961 (2002)
- "CSGN/c"[URL]
- Deveci, E, "Effect of clomiphene citrate on neonatal rat skin", Clin. Exp. Obstel. Gynecol, 27(3), pp.238~240 (2000)
- Dickey, R. P, "Development, pharmacology and clinical experience with clomiphene citrate", Hum. Reprod. Update, 2(6), pp.483~506 (1996)
- Duncan, D. B, "Multiple range and multiple F tests", Biometrics, 11, pp.1~42 (1955)
- Dziadek, M, "Preovulatory administration of clomiphene citrate to mice causes fetal growth retardation and neural tube defects (exencephaly) by an indirects maternal effect", Exp. Teratol, 47(4), pp.263~273 (2005)
- Elizur, S. E, "Drugs in fertility and fetal safety", Fertil. Steril, 89(6), pp.1595~1602 (2008)
- ESHRE Capri Workshop Group, "Anovulatory infertility", Hum. Reprod, 10, pp.1549~1553 (1995)
- Haring, D. A. J. P, "Acardius acephalus after induced ovulation: a case report", Clin. Teratol, 47(4), pp.257~262 (2005)
- Harmon, J. R., "Transplacental estrogen responses in the fetal rat: Increased uterine weight and ornithine decarboxylase activity", Dev. Pharmacol. Toxicol, 39(3), pp.253~260 (2005)
- Kennedy, J. L, "Ovulation induction. Obstet", Gynecol. Clin. North Am, 14(4), pp.831~864 (1987)
- Lerner- Geva, L, "Infertility, ovulation induction treatments and the incidence of breast cancer-A historical prospective cohort of Israeli Women", Breast Cancer Res. Treat, 100(2), pp.201~212 (2006)
- Macklon, N. S, "The science behind 25 years of ovarian stimulationfor in vitro fertilization", Endocr. Rev, 27(2), pp.170~207 (2006)
- Martikainen, H, "Effect of clomiphene citrate on prolactin and gonadotropin release during GnRH- analog treatment", Theriogenology, 66(6), pp.1560~1567 (2006)
- Mckenna, M, "Anti-oestrogens", Obstel. Gynaecol, 2, pp.545~561 (1988)
- Morris, J. M, "Postcoital antifertility agents and their teratogenic effects", Contraception, 2, pp.85~97 (1970)
- Motta, C. M, "Effects of clomiphene citrate on early pregnancy in guinea pigs", J. Reprod. Fertil, 92, pp.65~73 (1991)
- Orgeas, C. C, "Breast cancer incident after hormonal treatment of infertility in Sweden: a cohort study", Am. J. Obstel. Gynecol, 200(1), pp.72~77 (2009)
- Plourde, P. V, "Clomiphene in treatment of adolescent gynacomastia: Clinical and endocrine studies", Am. J. Dis. Child, 137(1), pp.1080~1082 (1983)
- Randal, J. M, "The effects of clomiphene citrate upon ovulation and endocrinology when administered to patients with unexplained infertility", Hum. Reprod, 6(5), pp.659~664 (1991)
- Schardein, J. L, "Congenital abnormalities and harmones during pregnancy: A clinical review", Clin. Teratol, 22(3), pp.251~270 (1980)