

Effect of Clomiphene Citrate on The Kidney of Adult Female Wister Rats with Regular Estrous Cycle
Abstract
The aim of this study is to evaluate and assess the Effect of Clomiphene citrate on kidney of adult female wistar rats with regular estrous cycle. A total of sixteen (16) 10 weeks old healthy female Wistar rats were purchased for the purpose of this study. Group 1(Control) (12 weeks old female rats; control): The animals in this group were not exposed to any experimental agent/drug. Group 2 (12 weeks old female rats; test): The animals in this group were exposed to the test drug (Clomiphene citrate 1mg) for 11 consecutive days. Group 3 (12 weeks old female rats; test): The animals in this group were /exposed to the test drug (Clomiphene citrate 2mg) for 11 consecutive days. Group 4 (12 weeks old female rats; test): The animals in this group were exposed to the test drug (Clomiphene citrate 5 mg) for 11 consecutive days. The test group rats were treated with Clomiphene Citate (30 mg body weight daily dissolved in required quantity of normal saline. Vaginal smear method to determent the estrous cycle of the rats was as documented.Vaginal smears were obtained from all rats to determine whether they had regular cycles for three cycles before drug administration. At the end of the 11th day of drug administration, vagina smear was carried out and the rats were sacrificed by cervical dislocation. Histological processing was done following the standard histological method. The result reveals that effect of different doses of Clomiphene citrate on kidney weight for regular estrous cycle. There were non significant (p>0.05) changes in organ weight from 0.80±0.25g for control to 0.97±0.07, 0.93±0.09 and 1.03±0.19g for group B, group C and group D respectively. Histology of the kidney showed degenerated glomerulus with demote spaces, mild degeneration of the glomerulus and mild leukocytic infiltration in some groups. It is concluded from the result of the present work that Clomiphene citrate induced kidney injury via its oxidative stress.
References
Al-Amoudi, W. M. (2012). Biochemical and Histological effects of clomiphene citrate on liver of female albino rat. J. Am. Sci, 8(5), 646–651.
Allen, R. E., Palopoli, F. P., & Schumann, E. L. (1959). Van Campen MG Jr: U. S. Patent, 2(914), 561,.
Amsterdam, E. (2012). Sponsored 3rd PCOS consensus workshop Group. Consensus on women’s health aspects of polycystic ovary syndrome (PCOS. Hum Reprod, 27, 14–24.
Bartges, J., & Polzin, D. (Eds.). (2011). Nephrology and urology of small animals. John Wiley & Sons.
Benshushan, A., Shushan, A., Paltiel, O., Mordel, N., & Laufer, N. (1995). Ovulation induction with clomiphene citrate complicated by deep vein thrombosis. European Journal of Obstetrics, Gynecology, and Reproductive Biology, 62(2), 261–262.
Blohm, T. R., Stevens, V. L., Kariya, T., & Alig, H. N. (1970). Effects of clomiphene cis and trans-isomers on sterol metabolism in the rat. Biochem Pharmacol, 19, 2231–2241.
Caldwell, G. W., Wu, W. N., Masucci, J. A., McKown, L. A., Gauthier, D., Jones, W. J., Leo, G. C., & Maryanoff, B. E. (2005). Metabolism and excretion of the antiepileptic/antimigraine drug, Topiramate in animals and humans. European Journal of Drug Metabolism and Pharmacokinetics, 30(3), 151–164.
Casper, R. F. (2009). Letrozole versus clomiphene citrate: which is better for ovulation induction? Fertility and Sterility, 92(3), 858–859.
Chamberlain, R. A., & Cumming, D. C. (1986). Pulmonary embolism during clomiphene therapy for infertility in a male: a case report. International Journal of Fertility, 31(3), 198–199.
Charles, D., Klein, T., Lunn, S. F., & Loraine, J. A. (1969). Clinical and endocrinological studies with the isomeric components of clomiphene citrate. BJOG: An International Journal of Obstetrics and Gynaecology, 76(12), 1100–1110.
Chua, M. E., Escusa, K. G., Luna, S., Tapia, L. C., & Difitas, B. (2013). Revisiting oestrogen antagonists (clomiphene and tamoxifen) as medical empiric therapy for idiopathic male infertility: A metaanalysis. Androl, 1, 749–757.
Clark, J. H., & Guthrie, S. C. (1981). Agonistic and antagonistic effects of clomiphene citrate and its isomers. Biology of Reproduction, 25(3), 667–672.
Cohen, J. (2003). A short review of ovarian stimulation in assisted reproductive techniques. Reproductive Biomedicine Online, 6(3), 361–366.
Couse, J. F., Yates, M. M., Walker, V. R., & Korach, K. S. (2003). Characterization of the hypothalamic-pituitary-gonadal axis in estrogen receptor (ER) null mice reveals hypergonadism and endocrine sex reversal in females lacking ERα but not ERβ. Molecular Endocrinology, 17(6), 1039–1053.
Crabbs, T. A., & McDorman, K. S. (2018). Brief synopsis: Review of Renal Tubule and Interstitial Anatomy and Physiology and renal INHAND, SEND, and DIKI nomenclature. Toxicologic Pathology, 46(8), 920–924.
Duran, J. R., 3rd, & Raja, M. L. (2007). Myocardial infarction in pregnancy associated with clomiphene citrate for ovulation induction: a case report. The Journal of Reproductive Medicine, 52(11), 1059–1062.
Fischer, C. D., Wachoski-Dark, G. L., Grant, D. M., Bramer, S. A., & Klein, C. (2018). Interferon epsilon is constitutively expressed in equine endometrium and up-regulated during the luteal phase. Animal Reproduction Science, 195, 38–43.
Fitzpatrick, S. L. (1999). Effect of estrogen agonists and antagonists on induction of progesterone receptor in a rat hypothalamic cell line. Endocrinology, 140(9), 3928–3937.
Fitzpatrick, S. L., Berrodin, T. J., Jenkins, S. F., Sindoni, D. M., Deecher, D. C., & Frail, D. E. (1999). Effect of estrogen agonists and antagonists on induction of progesterone receptor in a rat hypothalamic cell line. Endocrinology, 140(9), 3928–3937.
Franks, S., Adams, J., Mason, H., & Polson, D. (1985). Ovulatory disorders in women with polycystic ovary syndrome. Clinics in Obstetrics and Gynaecology, 12(3), 605–632.
Gades, M.D., Stern, J.S., van Goor, H., Nguyen, D., Johnson, P.R. and Kaysen, G.A. (1998). Estrogen accelerates the development of renal disease in female obese Zucker rats. Kidney Int., 53 (1):130-135.
Ghobadi, C., Amer, S., Lashen, H., Lennard, M. S., Ledger, W. L., & Rostami-Hodjegan, A. (2009). Evaluation of the relationship between plasma concentrations of en- and zuclomiphene and induction of ovulation in anovulatory women being treated with clomiphene citrate. Fertility and Sterility, 91(4), 1135–1140.
Ginai, M. (2015). Incorporating primary human renal proximal tubule cells into a hollow fibre bioreactor in the development of an in vitro model for pharmaceutical research. Loughborough University.
Goldman, J. M., Laws, S. C., Balchak, S. K., Cooper, R. L., & Kavlock, R. J. (2000). Endocrine-disrupting chemicals: prepubertal exposures and effects on sexual maturation and thyroid activity in the female rat. A focus on the EDSTAC recommendations. Critical Reviews in Toxicology, 30(2), 135–196.
Greenblatt, R. B., Barfield, W. E., Junget, E. C., & Roy, A. W. (1961). Induction of ovulation with MRL-41. JAMA, 178(101).
Maitra, C., & Hegde, R. (2020). Comparison of the role of letrozole & clomiphene citrate as a first line ovulation induction drug in infertile women with polycystic ovary syndrome. Indian Journal of Obstetrics and Gynecology Research, 7(1), 12–15.
Meijer, W. M., de Jong-Van den Berg, L. T. W., van den Berg, M. D., Verheij, J. B. G. M., & de Walle, H. E. K. (2006). Clomiphene and hypospadias on a detailed level: signal or chance? Birth Defects Research. Part A, Clinical and Molecular Teratology, 76(4), 249–252.
Pearse, G., Frith, J., Randall, K.J. and Klinowska, T. (2009). Urinary retention and cystitis associated with subcutaneous estradiol pellets in female nude mice. Toxicol. Pathol., 37 (2):227-234.
Reefhuis, J., Honein, M. A., Schieve, L. A., Rasmussen, S. A., & National Birth Defects Prevention Study. (2011). Use of clomiphene citrate and birth defects, National Birth Defects Prevention Study, 1997-2005. Human Reproduction (Oxford, England), 26(2), 451–457.
Rehfeld, A., Nylander, M., & Karnov, K. (2017). The Urinary System. In Compendium of Histology (pp. 495–515). Springer International Publishing.
Rossi, A., Gennari, A. G., Angileri, R., Martingano, P., Cavallaro, M., Pozzi-Mucelli, R., Zamboni, G., Bernardin, L., Contro, A., & Quaia, E. (2014). Computed Tomography. In Radiological Imaging of the Kidney (pp. 123–165). Springer Berlin Heidelberg.
Schlafer, D. H., & Foster, R. A. (2016). Female Genital System. In Jubb, Kennedy & Palmer’s Pathology of Domestic Animals: Volume 3 (pp. 358-464.e1). Elsevier.
Schreiber, E., Johnson, J. J., Plotz, E. J., & Weiner, M. (1966). Studies with 14C labeled clomiphene citrate. Clin Res, 14, 287.
Schulz, K.-D., Hölzel, F., & Bettendorf, G. (1971). The uptake and distribution of 14c-clomiphene citrate in different organs of Newborn female guinea pigs. European Journal of Endocrinology, 68(3), 605–613.
Sherbahn, R. (2015). Side effects and adverse effects of clomid, clomiphene citrate. Advanced Fertility Center of Chicago.
Shimono, J., Tsuji, H., Azuma, K., Hashiguchi, M., & Fujishima, M. (1998). A rare case of hepatic injury associated with ovarian hyperstimulation syndrome. The American Journal of Gastroenterology, 93(1), 123–124.
Silbiger, S. and Neugarten, J. (2008). Gender and human chronic renal disease. Gend. Med. 5A: S3-S10.
Sorensen, H. T., Pedersen, L., Skriver, M. V., Norgaard, M., Norgard, B., & Hatch, E. E. (2005). Use of clomifene during early pregnancy and risk of hypospadias: population based casecontrol study. BMJ, 330(7483), 126–127.
Stevenson, F.T., Wheeldon, C.M., Gades, M.D., Kaysen, G.A., Stern, J.S. and van Goor, H. (2000). Estrogen worsens incipient hypertriglyceridemic glomerular injury in the obese Zucker rat. Kidney Int., 57: 1927-1935.
Sutherland, R. L., & Murphy, L. C. (1982). Mechanisms of oestrogen antagonism by nonsteroidal antioestrogens. Molecular and Cellular Endocrinology, 25(1), 5–23.
Szutu, M., Morgan, D. J., McLeish, M., Phillipou, G., Blackman, G. L., Cox, L. W., & Dollman, W. (1989). Pharmacokinetics of intravenous clomiphene isomers. British Journal of Clinical Pharmacology, 27(5), 639–640.
Tatham, K., & Patel, K. (2010). Complete OSCE Skills for Medical and Surgical Finals. CRC Press.
Teramoto, S., & Kato, O. (2007). Minimal ovarian stimulation with clomiphene citrate: a large-scale retrospective study. Reproductive Biomedicine Online, 15(2), 134–148.
Trounson, A. O., Leeton, J. F., Wood, C., Webb, J., & Wood, J. (1981). Pregnancies in humans by fertilization in vitro and embryo transfer in the controlled ovulatory cycle. Science (New York, N.Y.), 212(4495), 681–682.
Vargyas, J. M., Morente, C., Shangold, G., & Marrs, R. P. (1984). The effect of different methods of ovarian stimulation for human in vitro fertilization and embryo replacement. Fertility and Sterility, 42(5), 745–749.
Wallach, E. E., & Adashi, E. Y. (1984). Clomiphene citrate: mechanism (s) and site (s) of action—a hypothesis revisited. Fertility and Sterility, 42(3), 331–344.
Weinz, C., Schwarz, T., Kubitza, D., Mueck, W., & Lang, D. (2009). Metabolism and excretion of rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and humans. Drug Metabolism and Disposition: The Biological Fate of Chemicals, 37(5), 1056–1064.
Yaşar, H. Y., & Ertuğrul, O. (2009). Clomiphene citrate-induced severe hypertriglyceridemia. Fertility and Sterility, 92(1), 396.e7-8.
Zellweger, R., Schwacha, M., & Chaudry, I. H. (2003). The immune/inflammatory system (pp. 377–390). CRC Press.
Zhan, E., Keimig, T., Xu, J., Peterson, E., Ding, J., Wang, F. and Yang, X.P. (2008). Dose-dependent cardiac effect of oestrogen replacement in mice post-myocardial infarction. Exp. Physiol., 93 (8): 982-993.
Refbacks
- There are currently no refbacks.