The Effect of Tamoxifen on the Fetal and Neonatal Ovarian Follicles Development in Rats

Document Type : Original Article

Authors

1 Department of Pharmacology & Toxicology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran

2 Department of Histology and Embryology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran

Abstract

Objective(s)
The effect of tamoxifen as a selective estrogen receptor modulator which is widely used for treatment of early and metastatic breast cancer was investigated on the folliculogenesis in rat's fetuses and neonates.
Materials and Methods
The pregnant rats assigned into test and control groups. Control group received olive oil and treatment groups received either 17-β-estradiol (10 µg/kg/day) or tamoxifen (0.4 mg/kg/day) between days 8-13 of pregnancy. On day 20th of pregnancy the rats euthanized and the blood samples were collected for determination of FSH, E2, and the fetuses fixed for histological studies. Another group of pregnant rats went forward to obtain their neonates and we euthanized the neonates and the genital system was collected for further histopathological analyses on day 5th.
Results
The histological examinations of the fetus’s and neonate's ovaries and biochemical data showed significant changes in the rats which treated with tamoxifen. The absence of folliculogenesis and an increase in E2 level in tamoxifen-treated group which accompanied with sharp decrease of FSH level in comparison with the control group were demonstrated. By contrary, E2 treated group showed a positive progress in development in terms of the formation of secondary follicles and also supportive connective tissues in comparison with the control group.
Conclusion
This  study  supports  the  previous  findings  showing  that  tamoxifen  has  effects  on  the development of ovaries and therefore, it should be avoided or used with great caution in pregnant women.

Keywords


1. Garrido-Gracia JC, Gordon A, Bellido C, Aguilar R, Barranco I, Millan Y, et al.The integrated action of oestrogen receptor isoforms and sites with progesterone receptor in the gonadotrope modulates LH secretion: evidence from tamoxifen-treated ovariectomized rats. J Endocrinol 2007; 193:107-119.
 2. Nichols M. The fight against tamoxifen resistance in breast cancer therapy: a new target in the battle? Mol Interv 2007; 7:6-13.
3. Rajah R, Glaser EM, Hirshfield AN. The changing architecture of the neonatal rat ovary during histogenesis. Dev Dyn 1992; 194:177– 192.
4. Al-Bader M. Estrogen receptors alpha and beta in rat placenta: detection by RT-PCR, real time PCR and Western blotting. Reprod Biol Endocrinol 2006; 4:13.
5. Hiroi H, Inoue S, Watanabe T, Goto W, Orimo A, Momoeda M, et al. Differential immunolocalization of estrogen receptor alpha and beta in rat ovary and uterus. J Mol Endocrinol 1999; 22:37-44.
6. Sar M, Welsch F. Differential expression of ERα and β in the rat ovary. Endocrinology 1999; 140:963-971.
7. Mc Ilroy M, Fleming FJ, Buggy Y, Hill AD, Young LS. Tamoxifen-induced ER-alpha-SRC-3 interaction in HER2 positive human breast cancer; a possible mechanism for ER isoform specific recurrence. Endocr Relat Cancer 2006; 13:1135-1145.
8. Kang Y, Cortina R, Perry RR.   Role of c-myc in tamoxifen-induced apoptosis estrogen-independent breast cancer cells. J Natl Cancer Inst 1996; 88:279-284.
9. Medlock  KL,  Branham  WS,  Sheehan  DM.  Effects  of  toremifene  on  neonatal  rat  uterine  growth  and differentiation. Biol Reprod 1997; 56:1239-1244.
10.  Poulet FM, Roessler ML,Vancutsem PM. Initial uterine alterations caused by developmental exposure to tamoxifen. Reprod Toxicol 1997; 11:815-822.
11.  Deveci E, Onen A, Tacar O, Yildirim A.The effect of tamoxifen on the neonatal development of rat glans penis. Clin Exp Obstet Gynecol 1997; 24:237-239.
12.  Jung EY, Lee BJ, Yun YW, Kang JK, Baek IJ, Jurg MY, Lee YB, et al. Effects of exposure to genistein and estradiol on reproductive development in immature male mice weaned from dams adapted to a soy-based commercial diet. J Vet Med Sci 2004; 66:1347-1354.
13.  Clarke DO, Griffey KI, Buelke-Sam J, Francis PC. The selective estrogen receptor modulator, raloxifene: reproductive  assessments  following  preimplantation  exposure  in  mated  female  rats.  Reprod  Toxicol  1998; 12:247-259.
14.  Karlsson S. Histopathology and histomorphometry of the urogenital tract in 15-month old male and female rats treated neonatally with SERMs and estrogens. Exp Toxicol Pathol 2006; 58:1-12.
15.  Robinson   SP,   Langan-Fahey   SM,   Johnson   DE,   Jordan   VC.   Metabolites,   pharmacodynamics,   and pharmacokinetics of tamoxifen in rats and mice compared to the breast cancer patient. Drug Metab Dispos 1991; 19:36-43.
16.  Suckow  MA,  Weisbroth  HS,  Franklin  CL.  The  laboratory rat.  Amsterdam: Academic Press: College  of Laboratory Animal Medicine Science, Elsevier; 2006.
17.  Matsuura  S,  Itakura  A,  Ohno  Y,  Nakashima  Y,  Murata  Y,  Takeuchi  M,  et  al.  Effects  of  estradiol administration on feto-placental growth in rat. Early Hum Dev 2004; 77:47-56.
18.  Acar D, Cayan S, Aktas S, Tek M, Akbay E. The effect of tamoxifen on bladder functions and histology, and the role of estrogen receptor beta in a rat chemical cystitis model. Neurourol Urodyn 2007; 26:309-316.
19.  Liu X, Pisha E, Tonetti DA, Yao D, Li Y, Yao J, et al.Antiestrogenic and DNA damaging effects induced by tamoxifen and toremifene metabolites. Chem Res Toxicol 2003; 16:832-837.
20.  White IN. Anti-oestrogenic drugs and endometrial cancers. Toxicol Lett 2001; 120:21-29.
21.  Nazarewicz RR, Zenebe WJ, Parihar A, Larson SK, Alidema E, Choi J, et al. Tamoxifen induces oxidative stress  and  mitochondrial  apoptosis  via  stimulating  mitochondrial  nitric  oxide  synthase.  Cancer  Res  2007; 67:1282-1290.
22.  Geraldes P, Gosselin H, Tanguay JF, Clement R, Calderone A. Tamoxifen treatment of myocardial infracted female rats exacerbates scar formation. Pflugers Arch 2007; 454:385-393.
23.  Tsang SY, Yao X, Chan HY, Chan FL, Leung CS, Yung LM, et al. Tamoxifen and estrogen attenuate enhanced vascular reactivity induced by estrogen deficiency in rat carotid arteries. Biochem Pharmacol 2007; 73:1330-1339.
24.  Castillo  C,  Ceballos  G,  Rodriguez  D,  Villanueva  C,  Medina  R,  Lopez  J,  et  al.  Effects  of  estradiol  on phenylephrine contractility associated with intracellular calcium release in rat aorta. Am J Physiol Cell Physiol 2006; 291:1388-1394.
25.  Cavalieri E, Frenkel K, Liehr JG, Rogan E, Roy D. Estrogens as endogenous genotoxic agents-DNA adducts and mutations. J Natl Cancer Inst Monog 2000; 27:75-93.
26.  Huseby RA. Demonstration of a direct carcinogenic effect of estradiol on leydig cells of the mouse. Cancer Res 1980; 40:1006-1013.
27.  Stack  DE,  Byun  J,  Gross  ML,  Rogan  EG,  Cavalieri  EL.  Molecular  characteristics  of  catechol  estrogen quinones in reactions with deoxyribonucleosides. Chem Res Toxicol 1996; 9:851-859.
28.  Haeger  P,  Andres  ME,  Forray  MI,  Daza  C,  Araneda  S,  Gysling  K.  Estrogen  receptors  alpha  and  beta differentially regulate the transcriptional activity of the urocortin gene. J Neurosci 2006; 26:4908-4916.
29.  Okada A, Ohta Y, Buchanan DL, Sato T, Inoue S, Hiroi H, et al. Changes in ontogenetic expression of estrogen receptor alpha and not of estrogen receptor beta in the female rat reproductive tract. J Mol Endocrinol 2002; 28:87-97.
30.  Kristensen CA, Hamberg LM, Hunter GJ, Roberge S, Kierstead D, Wolf GL, et al. Changes in vascularization of human breast cancer xenografts responding to antiestrogen therapy. Neoplasia 1999; 1:518-525.
31.  Murakami T, Sato A, Inatani M, Sakurai H, Yumoto R, Nagai J, et al. Effect of neonatal exposure to 17 beta- estradiol and tamoxifen on hepatic CYP3A activity in developmental periods in rat. Drug Metab Pharmacokinet 2004; 19:96-102.
32.  Terada S, Uchide K, Suzuki N, Akasofu K. A follicular cyst during tamoxifen therapy in a premenopausal breast cancer woman.  Gyncol Obstet Invest 1993; 5:62-64.