Hypothalamus-pituitary-thyroid axis disruption in rats with breast cancer is related to an altered endogenous oxytocin/insulin-regulated aminopeptidase (IRAP) system.

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-ß-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.

Doxazosin blockade of alpha 1-adrenergic receptors increases rat serum progesterone levels: a putative role of ovarian angiotensin III in steroidogenesis.

OBJECTIVE: To analyze the role of the local renin-angiotensin system (RAS) in the female reproductive system to modulate ovarian steroidogenesis and its relationship with alpha(1)adrenergic receptors. DESIGN: Observational study. SETTING: University laboratory. ANIMAL(S): Adult female Wistar rats treated with doxazosin (10 mg/kg) or vehicle for 15 days. INTERVENTION(S): Samples from the whole right ovary were dissected after perfusion with saline. The soluble and membrane-bound fractions were obtained from these samples. Also, blood samples were used to obtain the serum. MAIN OUTCOME MEASURE(S): Fluorometric measurement of soluble and membrane-bound RAS-regulating proteolytic regulatory enzyme activities by using arylamide derivatives as substrates. Time-resolved fluoroimmunoassay of serum E(2) and P. RESULT(S): alpha(1)Adrenergic receptor blockade increases ovarian soluble and membrane-bound aminopeptidase A and decreases membrane-bound aminopeptidase N and aminopeptidase B. Furthermore, serum P levels increased, whereas serum E(2) did not change. CONCLUSION(S): Ovarian P production, at least in the rat, is regulated by noradrenaline through a mechanism of action in which the RAS is involved, with a main role for angiotensin III.