Hypothalamus–pituitary–thyroid axis disruption in rats with breast cancer is related to an altered endogenous oxytocin/insulin-regulated aminopeptidase (IRAP) system
- 139 Downloads
Associations of breast cancer with diseases of the thyroid have been repeatedly reported, but the mechanism underlying this association remains to be elucidated. It has been reported that oxytocin (OXT) attenuates the thyroid-stimulating hormone (TSH) release in response to thyrotrophin-releasing hormone (TRH) and decreased plasma levels of TSH as well as the thyroid hormones by an effect mediated by the central nervous system. Oxytocinase (IRAP) is the regulatory proteolytic enzyme reported to hydrolyze OXT. Changes in IRAP activity have been reported in both human breast cancer and N-methyl-nitrosourea (NMU)-induced rat mammary tumours. Here, we measure IRAP activity fluorometrically using cystyl-β-naphthylamide as the substrate, in the hypothalamus–pituitary–thyroid axis together with the circulating levels of OXT, and its relationship with circulating levels of TSH and free thyroxine (fT4), as markers of thyroid function in control rats and rats with breast cancer induced by NMU. We found decreased thyroid function in rats with breast cancer induced by NMU, supported by the existence of lower serum circulating levels of both TSH and fT4 than their corresponding controls. Concomitantly, we found a decrease of hypothalamic IRAP activity and an increase in circulating levels of OXT. We propose that breast cancer increases OXT pituitary release by decreasing its hypothalamic catabolism through IRAP activity, probably due to the alteration of the estrogenic endocrine status. Thus, high circulating levels of OXT decreased TSH release from the pituitary, and therefore, of thyroid hormones from the thyroid, supporting the association between breast cancer and thyroid function disruption.
KeywordsN-Methyl nitrosourea Thyroid-stimulating hormone Free thyroxine Oxytocin Oxytocinase Thyroid Breast cancer
This work was supported by Junta de Andalucía through PAI BIO-296, Universidad de Jaén (grant number UJA2003/014), and Instituto de Estudios Giennenses (IEG; grant number 135/24102006).
Conflicts of interest
- 14.Larsen PR, Davies TF. The thyroid gland. In: Wilson JD, Foster DW, Kronenberg HM, Larsen PR, editors. Textbook of endocrinology. Philadelphia: Saunders; 1998.Google Scholar
- 31.Garcia MJ, Martinez-Martos JM, Mayas MD, Carrera MP, De la Chica S, Cortes P, et al. Hormonal status modifies renin-angiotensin system-regulating aminopeptidases and vasopressin-degrading activity in the hypothalamus-pituitary-adrenal axis of female mice. Med Chem. 2008;4:336–47.PubMedCrossRefGoogle Scholar
- 32.Carrera MP, Ramirez-Exposito MJ, Garcia MJ, Mayas MD, Martinez-Martos JM (2008) Ovarian renin-angiotensin system is involved in progesterone overproduction in rats with mammary tumours induced by n-methyl nitrosourea (NMU). ASEICA S1Google Scholar
- 34.Carrera MP, Ramirez-Exposito MJ, Valenzuela MT, Garcia MJ, Mayas MD, Arias de Saavedra JM, et al. Pyrrolidon carboxypeptidase activities in the hypothalamus-pituitary-thyroid and hypothalamus-pituitary-ovary axes of rats with mammary gland cancer induced by N-methyl nitrosourea. Horm Metab Res. 2005;37:74–8.PubMedCrossRefGoogle Scholar