Hypothyroidism And Fertility: An Animal Model Follows Up In The Second-Generation

Document Type : Original Article


1 Department of Anatomy, Embryology and Histology, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran

2 Department of Epidemiology and Biostatistics, School of Public Health, Infertility and Reproductive Health Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran

3 Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran

4 Department of Medical Sciences, Macquarie University, Sydney, NSW, Australia


Objective: Hypothyroidism is known as the most common endocrine disorder. The prevalence of hypothyroidism in the female and male population is 2% and 0.2%, respectively. Maternal hypothyroidism is a defect in the thyroid hormones transition from the mother to the fetus. The present study was conducted to find whether maternal hypothyroidism affects the fertility of the second generation.
Materials and Methods: In this experimental study, twelve adult female rats weighting 180-220 g were randomly divided into case and control groups. Hypothyroidism was induced by dissolving 0.1 g/L of 6-n-propyl-2-thiouracil in drinking water toward the end of pregnancy and lactation. At the end of the breastfeeding period, the blood samples of female children were collected. Six healthy, mature, female rats were selected and kept until they reached maturity, and were then mated with male rats. After observing the female rats’ delivery, blood samples were collected from their male and female newborns and the healthy rats were selected.
Results: There was a significant difference in the volume and size of ovarian as well as in the number of secondary
follicles in comparison with the control group (P=0.025). However, there were no significant changes in the other parameters including the number of primary follicles, the number of Graafian follicles and sperm parameters. There was no significant decrease in the testicular volume and size, number of Leydig cells and seminiferous tubules diameter.
Conclusion: Maternal hypothyroidism has no significant effects on testicular tissue function, and sperm parameters in
the second generation, but can significantly reduce the rate of secondary follicles in the second generation female rats.


  1. El-Sayed MS, El Badawy A, Abdelmoneim RO, Mansour AE, Khalil MEM, Darwish K. Relationship between serum sialic acid concentration and diabetic retinopathy in Egyptian patients with type 2 diabetes mellitus. Benha Med J. 2018; 35(2): 257.
  2. Poppe K, Velkeniers B, Glinoer D. Thyroid disease and female reproduction. Clin Endocrinol (Oxf). 2007; 66(3): 309-321.
  3. Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis. 2010; 5: 17.
  4. Hou J, Yu P, Zhu H, Pan H, Li N, Yang H, et al. The impact of maternal hypothyroidism during pregnancy on neonatal outcomes: a systematic review and meta-analysis. Gynecol Endocrinol. 2016; 32(1): 9-13.
  5. Pop VJ, Kuijpens JL, van Baar AL, Verkerk G, van Son MM, de Vijlder JJ, et al. Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol (Oxf). 1999; 50(2): 149-155.
  6. Morreale de Escobar G, Obregón MJ, Escobar del Rey F. Is neuropsychological development related to maternal hypothyroidism or to maternal hypothyroxinemia? J Clin Endocrinol Metab. 2000; 85(11): 3975-3987.
  7. Klein RZ, Sargent JD, Larsen PR, Waisbren SE, Haddow JE, Mitchell ML. Relation of severity of maternal hypothyroidism to cognitive development of offspring. J Med Screen. 2001; 8(1): 18-20.
  8. Pop VJ, Brouwers EP, Vader HL, Vulsma T, van Baar AL, de Vijlder JJ. Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study. Clin Endocrinol (Oxf). 2003; 59(3): 282-288.
  9. Hamouli-Said Z, Tahari F, Hamoudi F, Hadj-Bekkouche F. Comparative study of the effects of pre and post natal administration of a thyroid drug on testicular activity in adult rat. Folia Histochem Cytobiol. 2007; 45 Suppl 1: S51-57.
  10. Saki F, Dabbaghmanesh MH, Ghaemi SZ, Forouhari S, Ranjbar Omrani G, Bakhshayeshkaram M. Thyroid function in pregnancy and its influences on maternal and fetal outcomes. Int J Endocrinol Metab. 2014; 12(4): e19378.
  11. Cabello G, Wrutniak C. Thyroid hormone and growth: relationships with growth hormone effects and regulation. Reprod Nutr Dev. 1989; 29(4): 387-402.
  12. Patel J, Landers K, Li H, Mortimer RH, Richard K. Delivery of maternal thyroid hormones to the fetus. Trends Endocrinol Metab. 2011; 22(5): 164-170.
  13. Blazer S, Moreh-Waterman Y, Miller-Lotan R, Tamir A, Hochberg Z. Maternal hypothyroidism may affect fetal growth and neonatal thyroid function. Obstet Gynecol. 2003; 102(2): 232-241.
  14. Mitchell ML, Klein RZ. The sequelae of untreated maternal hypothyroidism. Eur J Endocrinol. 2004; 151 Suppl 3: U45-48.
  15. Obregon MJ, Calvo RM, Escobar Del Rey F, Morreale de Escobar G. Ontogenesis of thyroid function and interactions with maternal function. Endocr Dev. 2007; 10: 86-98.
  16. Hapon MB, Gamarra-Luques C, Jahn GA. Short term hypothyroidism affects ovarian function in the cycling rat. Reprod Biol Endocrinol. 2010; 8: 14.
  17. Pirahanchi Y, Tariq MA, Jialal I. Physiology, thyroid. StatPearls. 2020. Available from: https://www.ncbi.nlm.nih.gov/books/ NBK519566/ (25 Apr 2021).
  18. Safarpour S, Zabihi E, Ghasemi-Kasman M, Nosratiyan N, Feizi F. Prenatal and breastfeeding exposure to low dose of diethylhexyl phthalate induces behavioral deficits and exacerbates oxidative stress in rat hippocampus. Food Chem Toxicol. 2021; 154: 112322.
  19. Dijkstra G, de Rooij DG, de Jong FH, van den Hurk R. Effect of hypothyroidism on ovarian follicular development, granulosa cell proliferation and peripheral hormone levels in the prepubertal rat. Eur J Endocrinol. 1996; 134(5): 649-654.
  20. Zertashia A, Jalali S, Ahmad L, Mirza A. Effect of hypothyroidism induced by propylthiouracil on ovarian function and structure in offspring from treated mothers (Rats). J Exp Zool. 2002; 293(4): 407-413.
  21. Ortega E, Rodriguez E, Ruiz E, Osorio C. Activity of the hypothalamo- pituitary ovarian axis in hypothyroid rats with or without triiodothyronine replacement. Life Sci. 1990; 46(6): 391-395. 22. Colella M, Cuomo D, Giacco A, Mallardo M, De Felice M, Ambrosino C. Thyroid hormones and functional ovarian reserve: systemic vs. peripheral dysfunctions. J Clin Med. 2020; 9(6): 1679.
  22. Aghajanova L, Stavreus-Evers A, Lindeberg M, Landgren BM, Sparre LS, Hovatta O. Thyroid-stimulating hormone receptor and thyroid hormone receptors are involved in human endometrial physiology. Fertil Steril. 2011; 95(1): 230-237.
  23. Sarkar D, Singh SK. Effect of neonatal hypothyroidism on prepubertal mouse testis in relation to thyroid hormone receptor alpha 1 (THRα1). Gen Comp Endocrinol. 2017; 251: 109-120.
  24. Al-Awdan AE-WA, Idrees SE, Shalaby SA, Mehlab EM, Mannawy SM. Prenatal and postnatal effects of hypothyroidism and thyroxin replacement on the development of rat testis. Am J Sci. 2014; 10(9).
  25. Francavilla S, Cordeschi G, Properzi G, Di Cicco L, Jannini EA, Palmero S, et al. Effect of thyroid hormone on the pre- and post-natal development of the rat testis. J Endocrinol. 1991; 129(1): 35-42.
  26. Canale D, Agostini M, Giorgilli G, Caglieresi C, Scartabelli G, Nardini V, et al. Thyroid hormone receptors in neonatal, prepubertal, and adult rat testis. J Androl. 2001; 22(2): 284-288.
  27. Valle LB, Oliveira-Filho RM, Romaldini JH, Lara PF. Pituitarytesticular axis abnormalities in immature male hypothyroid rats. J Steroid Biochem. 1985; 23(3): 253-257.
  28. Mendis-Handagama SM, Ariyaratne HB. Differentiation of the adult Leydig cell population in the postnatal testis. Biol Reprod. 2001; 65(3): 660-671.
  29. La Vignera S, Vita R, Condorelli RA, Mongioì LM, Presti S, Benvenga S, et al. Impact of thyroid disease on testicular function. Endocrine. 2017; 58(3): 397-407.
  30. Dick B, Koller C, Herzog B, Greenberg J, Hellstrom WJ. The role of hormones in male sexual function. Curr Sex Health Rep. 2020: 1-12.
  31. Amer MH, Thuwain MM, AL-Snafi A. Investigation of thyroids dysfunction among infertile women in Nasiriyah city. Int J Curr Pharm Res. 2020; 12(5): 31-34.
  32. Koyyada A, Orsu P. Role of hypothyroidism and associated pathways in pregnancy and infertility: Clinical insights. Tzu Chi Med J. 2020; 32(4): 312-317.