Volume 21, Issue 1 (January 2023)                   IJRM 2023, 21(1): 71-82 | Back to browse issues page

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Shaaban Z, Derakhshanfar A, Jafarzadeh Shirazi M R, Zamiri M J, Moayedi J, Vahedi M et al . The effects of letrozole-induced maternal hyperandrogenism on sexual behaviors, testicular histology, and serum biochemical traits in male offspring rats: An experimental study. IJRM 2023; 21 (1) :71-82
URL: http://ijrm.ir/article-1-2477-en.html
The effects of letrozole-induced maternal hyperandrogenism on sexual behaviors, testicular histology, and serum biochemical traits in male offspring rats: An experimental study
Zahra Shaaban1 , Amin Derakhshanfar * 2, Mohammad Reza Jafarzadeh Shirazi1 , Mohammad Javad Zamiri1 , Javad Moayedi3 , Mahjoob Vahedi4 , Abouzar Valizadeh4
1- Department of Animal Sciences, College of Agriculture, Shiraz University, Shiraz, Iran.
2- Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran. Center of Comparative and Experimental Medicine, Shiraz University of Medical Sciences, Shiraz, Iran. , derakhshanfar@sums.ac.ir
3- Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran. Center of Comparative and Experimental Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
4- Center of Comparative and Experimental Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
Abstract:   (786 Views)
Background: Intrauterine endocrine abnormalities have profound effects on the development of physiological disorders.
Objective: This study aimed to assess the effects of in utero exposure to letrozole (an aromatase inhibitor) and its late consequences on the reproductive and metabolic performance of an adult male offspring.
Materials and Methods: 15 pregnant Sprague-Dawley rats (8 wk, 155 gr) were randomly assigned into 5 experimental groups (n = 3/each) and orally received either letrozole at doses of 0.25, 0.75, 1.00, and 1.25 mg/kg body weight (BW) or vehicle (control) on the gestation days of 16, 17, and 18. Pregnancy outcome, sexual behaviors on postnatal day 60, serum biochemical features, and the histopathology of testes were assessed in male offspring.
Results: Compared to control group, delayed labor (21.83 vs. 24.25, p < 0.0001) and reduced litter size (n = 12.25 vs. n = 2, p < 0.0001) were recorded in 1.25 mg/kg BW group. A reduction in high-density lipoprotein level and the elevation of testes weight, BW gain, anogenital distance, as well as the serum concentrations of testosterone, triglycerides, cholesterol, and glucose were observed in 1.25 mg/kg BW (p < 0.0001) and 1.00 mg/kg BW (p < 0.0001) groups in comparison to control. A larger number of anogenital female sniffing, pursuit, and mounting behaviors were also observed in 1.25 mg/kg BW group in comparison to control (p < 0.0001). Severe testicular defects including necrosis and disruption of the epithelium of seminiferous tubules, sloughing of epithelial cells, and spermatogenesis arrest were observed in letrozole-treated groups, in a dose-dependent manner.
Conclusion: Maternal exposure to letrozole can adversely affect the reproductive and metabolic performance of male offspring rats, suggesting an incomplete sex differentiation.
Keywords: Androgens, Aromatase inhibitors, Rat, Sexual activities, Testes histopathology.
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Type of Study: Original Article | Subject: Reproductive Physiology
References
1. Olulana DI, Popoola C. Comparative effects of pre-gestational doses of clomiphene citrate versus letrozole on the heart of developing wistar rats. Anatomy Journal of Africa 2021; 10: 1871-1877.
2. Kar S. Current evidence supporting "letrozole" for ovulation induction. J Hum Reprod Sci 2013; 6: 93-98. [DOI:10.4103/0974-1208.117166] [PMID] [PMCID]
3. Yun J, Choi YS, Lee I, Won YB, Lee JH, Seo SK, et al. Comparison of congenital malformations among babies born after administration of letrozole or clomiphene citrate for infertility treatment in a Korean cohort. Reprod Toxicol 2018; 82: 88-93. [DOI:10.1016/j.reprotox.2018.10.006] [PMID]
4. Ramezani Tehrani F, Noroozzadeh M, Zahediasl S, Ghasemi A, Piryaei A, Azizi F. Prenatal testosterone exposure worsen the reproductive performance of male rat at adulthood. PloS One 2013; 8: e71705. [DOI:10.1371/journal.pone.0071705] [PMID] [PMCID]
5. Martin YH. Androgen action within the vomeronasal organ contributes to the sexual differentiation of the brain and behaviour [M.Sc. Thesis]. Memorial University of Newfoundland; 2021.
6. Gerardin DCC, Piffer RC, Garcia PC, Moreira EG, Pereira OCM. Effects of maternal exposure to an aromatase inhibitor on sexual behaviour and neurochemical and endocrine aspects of adult male rat. Reprod Fertil Dev 2008; 20: 557-562. [DOI:10.1071/RD07213] [PMID]
7. Arroyo MAM, Silva Santos PRD, de Oliveira MF, de Assis AC. Prolonged use of letrozole causes morphological changes on gonads in Galea spixii. Anim Reprod 2021; 18: e20200029. [DOI:10.1590/1984-3143-ar2020-0029] [PMID] [PMCID]
8. Onaolapo AY, Onaolapo OJ. A review of the impact of testosterone on brain and aging-related decline in brain behavioural function. Front Clin Drug Res-CNS Neurol Disord 2022; 10: 314-335. [DOI:10.2174/9789815040678122100009]
9. Macleod DJ, Sharpe RM, Welsh M, Fisken M, Scott HM, Hutchison GR, et al. Androgen action in the masculinization programming window and development of male reproductive organs. Int J Androl 2010; 33: 279-287. [DOI:10.1111/j.1365-2605.2009.01005.x] [PMID]
10. Reznikov A, Nosenko N, Tarasenko L. Early postnatal effects of prenatal exposure to glucocorticoids on testosterone metabolism and biogenic monoamines in discrete neuroendocrine regions of the rat brain. Comp Biochem Physiol Part C: Toxicol Pharmacol 2004; 138: 169-175. [DOI:10.1016/j.cca.2004.06.005] [PMID]
11. Cara AL, Henson EL, Beekly BG, Elias CF. Distribution of androgen receptor mRNA in the prepubertal male and female mouse brain. J Neuroendocrinol 2021; 33: e13063. [DOI:10.1111/jne.13063] [PMID] [PMCID]
12. Hughes IA, Deeb A. Androgen resistance. Best Practice & Research Clinical Endocrinology & Metabolism 2006; 20: 577-598. [DOI:10.1016/j.beem.2006.11.003] [PMID]
13. Dean A, Smith LB, Macpherson S, Sharpe RM. The effect of dihydrotestosterone exposure during or prior to the masculinization programming window on reproductive development in male and female rats. Int J Androl 2012; 35: 330-339. [DOI:10.1111/j.1365-2605.2011.01236.x] [PMID]
14. Huang G, Aroner SA, Bay CP, Gilman SE, Ghassabian A, Loucks EB, et al. Sex-dependent associations of maternal androgen levels with offspring BMI and weight trajectory from birth to early childhood. J Endocrinol Invest 2021; 44: 851-863. [DOI:10.1007/s40618-020-01385-4] [PMID] [PMCID]
15. Barker DJP. The origins of the developmental origins theory. Journal of Internal Medicine 2007; 261: 412-417. [DOI:10.1111/j.1365-2796.2007.01809.x] [PMID]
16. Tiboni GM, Marotta F, Rossi C, Giampietro F. Effects of the aromatase inhibitor letrozole on in utero development in rats. Hum Reprod 2008; 23: 1719-1723. [DOI:10.1093/humrep/den100] [PMID]
17. Shaaban Z, Tamadon A, Jafarzadeh Shirazi MR, Zamiri MJ, Derakhshanfar A. Maternal aromatase inhibition via letrozole altered RFamide-related peptide-3 and gonadotropin-releasing hormone expression in pubertal female rats. Iran J Basic Med Sci 2022; 25: 110-120. [DOI:10.21203/rs.3.rs-361961/v1]
18. Olvera-Hernández S, Chavira R, Fernández-Guasti A. Prenatal letrozole produces a subpopulation of male rats with same-sex preference and arousal as well as female sexual behavior. Physiol Behav 2015; 139: 403-411. [DOI:10.1016/j.physbeh.2014.11.060] [PMID]
19. Chu X, Ågmo A. Sociosexual interactions in rats: Are they relevant for understanding human sexual behavior? Int J Psychol Res 2016; 9: 76-95. [DOI:10.21500/20112084.2339]
20. Hernández A, Olvera-Hernández S, Fernández-Guasti A. Lack of interaction between prenatal stress and prenatal letrozole to induce same-sex preference in male rats. Physiol Behav 2020; 224: 113042. [DOI:10.1016/j.physbeh.2020.113042] [PMID]
21. Vari CE, Ősz BE, Perian M, Mărușter MS, Miklos A, Bosa P, et al. Do aromatase inhibitors reduce fertility and impair sexual behaviour in an androgen doping model in rats? Farmacia 2017; 65: 336-342.
22. Turner KJ, Morley M, Atanassova N, Swanston ID, Sharpe RM. Effect of chronic administration of an aromatase inhibitor to adult male rats on pituitary and testicular function and fertility. J Endocrinol 2000; 164: 225-238. [DOI:10.1677/joe.0.1640225] [PMID]
23. Chinnathambi V, Balakrishnan M, Yallampalli C, Sathishkumar K. Prenatal testosterone exposure leads to hypertension that is gonadal hormone-dependent in adult rat male and female offspring. Biol Reprod 2012; 86: 137. [DOI:10.1095/biolreprod.111.097550] [PMID] [PMCID]
24. Abdelaziz AS, Kamel MA, Ahmed AI, Shalaby SI, El-Darier SM, Beshbishy AM, et al. Chemotherapeutic potential of epimedium brevicornum extract: The cGMP-specific PDE5 inhibitor as anti-infertility agent following long-term administration of tramadol in male rats. Antibiotics 2020; 9: 318. [DOI:10.3390/antibiotics9060318] [PMID] [PMCID]
25. 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:10.1016/j.ygcen.2016.02.028] [PMID]
26. Peivandi S, Jafarpour H, Abbaspour M, Ebadi A. Effect of letrozole on spermogram parameters and hormonal profile in infertile men: A clinical trial study. Endocr Regul 2019; 53: 231-236. [DOI:10.2478/enr-2019-0023] [PMID]
27. Rojas-García PP, Recabarren MP, Sarabia L, Schön J, Gabler C, Einspanier R, et al. Prenatal testosterone excess alters Sertoli and germ cell number and testicular FSH receptor expression in rams. Am J Physiol Endocrinol Metab 2010; 299: E998-E1005. [DOI:10.1152/ajpendo.00032.2010] [PMID]
28. Bormann CL, Smith GD, Padmanabhan V, Lee TM. Prenatal testosterone and dihydrotestosterone exposure disrupts ovine testes development. Reproduction 2011; 142: 167-173. [DOI:10.1530/REP-10-0210] [PMID] [PMCID]
29. Robertson KM, O'Donnell L, Jones ME, Meachem SJ, Boon WC, Fisher CR, et al. Impairment of spermatogenesis in mice lacking a functional aromatase (cyp 19) gene. Proc Natl Acad Sci USA 1999; 96: 7986-7991. [DOI:10.1073/pnas.96.14.7986] [PMID] [PMCID]
30. Misiakiewicz K, Kolasa A, Kondarewicz A, Marchlewicz M, Wiszniewska B. Expression of the c-Kit receptor in germ cells of the seminiferous epithelium in rats with hormonal imbalance. Reprod Biol 2013; 13: 333-340. [DOI:10.1016/j.repbio.2013.10.004] [PMID]
31. 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: 677-684. [DOI:10.5603/FHC.2011.0091] [PMID]
32. Demissie M, Lazic M, Foecking EM, Aird F, Dunaif A, Levine JE. Transient prenatal androgen exposure produces metabolic syndrome in adult female rats. Am J Physiol Endocrinol Metab 2008; 295: E262-E268. [DOI:10.1152/ajpendo.90208.2008] [PMID] [PMCID]
33. Lazic M, Aird F, Levine JE, Dunaif A. Prenatal androgen treatment alters body composition and glucose homeostasis in male rats. J Endocrinol 2011; 208: 293-300. [DOI:10.1677/JOE-10-0263] [PMID] [PMCID]
34. Agoreyo FO, Okeke OG. Quantitative evaluation of serum oestrogen levels in the three trimesters of pregnancy in albino rat. NISEB Journal 2014; 14: 98-100.
35. Tiboni GM, Ponzano A. Fetal safety profile of aromatase inhibitors: Animal data. Reprod Toxicol 2016; 66: 84-92. [DOI:10.1016/j.reprotox.2016.09.016] [PMID]
36. Wolf CJ, Hotchkiss A, Ostby JS, LeBlanc GA, Gray Jr LE. Effects of prenatal testosterone propionate on the sexual development of male and female rats: A dose-response study. Toxicol Sci 2002; 65: 71-86. [DOI:10.1093/toxsci/65.1.71] [PMID]
37. Kafali H, Iriadam M. A novel tocolytic agent: Effects of letrozole on gestational length and parturition time. Am J Perinatol 2007; 24: 323-326. [DOI:10.1055/s-2007-981435] [PMID]
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