title: Hypothalamus-pituitary-thyroid axis disruption in rats with breast cancer is related to an altered endogenous oxytocin/insulin-regulated aminopeptidase (IRAP) system.
abstract: 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.
authors.affiliation: Experimental and Clinical Physiopathology Research Group, Department of Health Sciences, Faculty of Experimental and Health Sciences, University of Jaén, Campus Universitario Las Lagunillas, 23071, Jaén, Spain. pcarrera@ujaen.es
authors.forename: María Pilar
authors.initials: MP
authors.lastname: Carrera-González
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Ramírez-Expósito
authors.forename: Jose Manuel Arias
authors.initials: JM
authors.lastname: de Saavedra
authors.forename: Rafael
authors.initials: R
authors.lastname: Sánchez-Agesta
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Mayas
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Martínez-Martos
mesh_terms: D000818:Animals; D010122:Cystinyl Aminopeptidase / Q000502:physiology*; D005260:Female; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology*; D008325:Mammary Neoplasms, Experimental / Q000503:physiopathology*; D010121:Oxytocin / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013961:Thyroid Gland / Q000503:physiopathology*; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood
chemical_list: D010121:Oxytocin; D013972:Thyrotropin; D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase; D013974:Thyroxine