Morphological and morphometric changes and epithelial apoptosis are induced in the rat epididymis by long-term letrozole treatment
The epididymis is an organ that plays a key role in sperm maturation. The aim of this study was to examine the association between the chronic treatment of mature male rats with letrozole and morphological evaluation and morphometric values of epididymis as well as changes in the number of apoptotic cells in epididymal epithelium. Adult rats were treated with letrozole for 6 months and the epididymis weight, morphology, morphometric values and the number of apoptotic cells in the epithelium were examined. Long-term aromatase inhibition resulted in presence of intraepithelial clear vacuoles, hyperplasia of clear cells and a hyperplastic alteration in the epithelium known as a cribriform change. Moreover, changes in diameters of the epididymal duct and the epididymal lumen and changes in the epididymal epithelium height were observed. The number of apoptotic epithelial cells was increased in letrozole-treated group. It can be indicated that chronic treatment with letrozole can affect morphology, morphometric values and apoptosis in the epididymis of adult male rats. Observed changes are similar to that observed in the aging processes and may also be important for patients treated with aromatase inhibitors.
Leir S-H, Browne JA, Eggener SE, Harris A. Characterization of primary cultures of adult human epididymis epithelial cells. Fertil Steril 2015;103:647-54. DOI: https://doi.org/10.1016/j.fertnstert.2014.11.022
De Mello Santos T, Hinton BT. We, the developing rete testis, efferent ducts, and Wolffian duct, all hereby agree that we need to connect. Andrology 2019;7:581-7. DOI: https://doi.org/10.1111/andr.12631
Murashima A, Bingfang X, Hinton BT. Understanding normal and abnormal development of the Wolffian/epididymal duct by using transgenic mice. Asian J Androl 2015;17:749-55.
Cornwall GA. New insights into epididymal biology and function. Hum Reprod Update 2009;15:213-27. DOI: https://doi.org/10.1093/humupd/dmn055
Joseph A, Shur BD, Hess RA. Estrogen, efferent ductules, and the epididymis. Biol Reprod 2011;84:207-17. DOI: https://doi.org/10.1095/biolreprod.110.087353
Jelinsky SA, Turner TT, Bang HJ, Finger JN, Solarz MK, Wilson E, et al. The rat epididymal transcriptome: comparison of segmental gene expression in the ray and mouse epididymides. Biol Reprod 2007;76:561-70. DOI: https://doi.org/10.1095/biolreprod.106.057323
Arrotéia KF, Garcia PV, Barbieri MF, Justino ML, Pereira LAV. The epididymis: embryology, structure, function and its role in fertilization and infertility. IntechOpen; 2012. DOI: https://doi.org/10.5772/35847
Hinton BT, Robaire B. The epididymis. In: Plant T, Zeleznik A, editors. Knobil and Neill's physiology of reproduction. New York: Elsevier; 2015. p. 691-772. DOI: https://doi.org/10.1016/B978-0-12-397175-3.00017-X
Elfgen V, Mietens A, Mewe M, Hau T, Middendorff R. Contractility of the epididymal duct: function, regulation and potential drug effects. Reproduction 2018;156:125-141. DOI: https://doi.org/10.1530/REP-17-0754
De Ronde W, Pols H, van Leeuwen J, de Jong FH. The importance of oestrogens in males. Clin Endocrinol 2003;58:529-52. DOI: https://doi.org/10.1046/j.1365-2265.2003.01669.x
Hess RA. Disruption of estrogen receptor signaling and similar pathways in the efferent ductules and initial segment of the epididymis. Spermatogenesis 2014;4:e979103. DOI: https://doi.org/10.4161/21565562.2014.979103
Wiszniewska B. Primary culture of the rat epididymal epithelial cells as a source of oestrogen. Andrologia 2002;34:180-7. DOI: https://doi.org/10.1046/j.1439-0272.2002.00495.x
Carpino A, Romeo F, Rago V. Aromatase immunolocalization in human ductuli efferentes and proximal ductus epididymis. J Anat 2004;204:217-20. DOI: https://doi.org/10.1111/j.0021-8782.2004.00272.x
Parlevliet JM, Pearl CA, Hess MF, Famula TR, Roser JF. Immunolocalization of estrogen and androgen receptors and steroid concentrations in the stallion epididymis. Theriogenology 2006;66:755-65. DOI: https://doi.org/10.1016/j.theriogenology.2005.12.013
Kolasa A, Wiszniewska B, Marchlewicz M, Wenda-Rózewicka L. Localisation of oestrogen receptors (ERalpha and ERbeta) in the human and rat epididymides. Folia Morphol (Warsz) 2003;62:467-9.
Verma R, Krishna A. Effect of Letrozole, a selective aromatase inhibitor, on testicular activities in adult mice: Both in vivo and in vitro study. Gen Comp Endocrinol 2017;241:57-68. DOI: https://doi.org/10.1016/j.ygcen.2016.02.028
Patry G, Jarvi K, Grober ED, Lo KC. Use of the aromatase inhibitor letrozole to treat male infertility. Fertil Steril 2009;92:829. DOI: https://doi.org/10.1016/j.fertnstert.2009.05.014
Zhao D, Pan L, Zhang F, Pan F, Ma J, Zhang X, Liu Y. Successful use of aromatase inhibitor letrozole in NOA with an elevated FSH level: a case report. Andrologia 2014;46:456-7. DOI: https://doi.org/10.1111/and.12122
Cavallini G, Biagiotti G, Bolzon E. Multivariate analysis to predict letrozole efficacy in improving sperm count of non-obstructive azoospermic and cryptozoospermic patients: a pilot study. Asian J Androl 2013;15:806-11. DOI: https://doi.org/10.1038/aja.2013.99
Gregoriou O, Bakas P, Grigoriadis C, Creatsa M, Hassiakos D, Creatsas G. Changes in hormonal profile and seminal parameters with use of aromatase inhibitors in management of infertile men with low testosterone to estradiol ratios. Fertil Steril 2012;98:48-51. DOI: https://doi.org/10.1016/j.fertnstert.2012.04.005
Loves S, Ruinemans-Koerts J, de Boer H. Letrozole once a week normalizes serum testosterone in obesity-related male hypogonadism. Eur J Endocrinol 2008;158:741-7. DOI: https://doi.org/10.1530/EJE-07-0663
Nordman IC, Dalley DN. Breast cancer in men - should aromatase inhibitors become first-line hormonal treatment? Breast J 2008;14:562-9. DOI: https://doi.org/10.1111/j.1524-4741.2008.00648.x
Kumar H, Jayaraman M, Verma A, Modi KM. Letrozole as a booster therapy in growth hormone deficiency. Indian Pediatr 2009;46:625-7.
Kondarewicz A, Kolasa A, Zawiślak B, Baranowska-Bosiacka I, Marchlewicz M, Wenda-Różewicka L, et al. Testis morphology in rats chronically treated with letrozole, an aromatase inhibitor. Folia Histochem Cytobiol 2011;49:677-84. DOI: https://doi.org/10.5603/FHC.2011.0091
Marchlewicz M, Szypulska-Koziarska D, Baranowska-Bosiacka I, Duchnik E, Wiszniewska B, Kruk J. The effect of pre- and postnatal exposure to a mixture daidzein and genistein on the reproductive system of male rats. Pomeranian J Life Sci 2020;66:5-12. DOI: https://doi.org/10.21164/pomjlifesci.550
Ansari AS, Hussain M, Khan SR, Badar A, Lohiya NK. Toxicity and mutagenicity evaluation following RISUG contraception reversal in rats. Int J Toxicol 2018;37:457-65. DOI: https://doi.org/10.1177/1091581818809473
Ning J, Rao T, Cheng F, Yu W-M, Ruan Y, Zhu S-M, et al. Effect of varicocelectomy treatmenton spermatogenesis and apoptosis via the induction of heat shockprotein 70 in varicocele induced rats. Mol Med Rep 2014;16:5406-12. DOI: https://doi.org/10.3892/mmr.2017.7239
Ezer N, Robaire B. Gene expression is differentially regulated in the epididymis after orchidectomy. Endocrinology 2003;144:975-88. DOI: https://doi.org/10.1210/en.2002-220705
Hess RA. Estrogen in the adult male reproductive tract: a review. Reprod Biol Endocrinol 2003;1:52. DOI: https://doi.org/10.1186/1477-7827-1-52
Cappon GD, Chapin RE, Hurtt ME, Wajnrajch MP, Burns-Naas LA. Impaired reproduction in adult male, but not female, rats following juvenile treatment with the aromatase inhibitor exemestane. Birth Defects Res B Dey Reprod Toxicol 2011;92:304-13. DOI: https://doi.org/10.1002/bdrb.20307
Serre V, Robaire B. Segment-specific morphological changes in aging Brown Norway rat epididymis. Biol Reprod 1998;58:497-513. DOI: https://doi.org/10.1095/biolreprod58.2.497
Hess RA, Bunick D, Lubahn DB, Zhou Q, Bouma J. Morphologic changes in efferent ductules and epididymis in estrogen receptor-alpha knockout mice. J Androl 2000;21:107-21.
Hess RA. Oestrogen in fluid transport and reabsorption in efferent ducts of the male reproductive tract. Rev Reprod 2000;5:84-92. DOI: https://doi.org/10.1530/revreprod/5.2.84
Cyr DG, Gregory M, Dube E, Dufresne J, Chan PT. Orchestration of occludins, claudins, catenins and cadherins as players involved in maintenance of the blood-epididymal barrier in animals and humans. Asian J Androl 2007;9:463-45. DOI: https://doi.org/10.1111/j.1745-7262.2007.00308.x
De Grava Kempinas W, Klinefelter GR. Interpreting histopathology in the epididymis. Spermatogenesis 2015;4:e979114. DOI: https://doi.org/10.4161/21565562.2014.979114
Hess RA, Fernandes SA, Gomes GR, Oliveira CA, Lazari MF. Estrogen and its receptors in efferent ductules and epididymis. J Androl 2011;32:600-13. DOI: https://doi.org/10.2164/jandrol.110.012872
Pilutin A, Misiakiewicz-Has K, Kolasa A, Baranowska-Bosiacka I, Marchlewicz M, Wiszniewska B. The immunoexpression of androgen receptor, estrogen receptors alpha and beta, vanilloid type 1 receptor and cytochrome p450 aromatase in rats testis chronically treated with letrozole, an aromatase inhibitor. Folia Histochem Cytobiol 2014;52:206-17. DOI: https://doi.org/10.5603/FHC.2014.0024
Hess RA, Bunick D, Lee KH, Bahr J, Taylor JA, Korach KS, et al. A role for oestrogens in the male reproductive system. Nature 1997;390:509-12. DOI: https://doi.org/10.1038/37352
Fan XP, Robaire B. Orchiectomy induces awave of apoptotic cell death in the epididymis. Endocrinology 1998;139:2128-36. DOI: https://doi.org/10.1210/endo.139.4.5888
Turner TT, Riley TA. p53 independent, region-specific epithelial apoptosis induced in the rat epididymis by deprivation of luminal factors. Mol Reprod Dev 1999;53:188-97. DOI: https://doi.org/10.1002/(SICI)1098-2795(199906)53:2<188::AID-MRD8>3.0.CO;2-O
- Abstract views: 72
- PDF: 37
- HTML: 0
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.