Hyperthyroidsm modulates hypotalamic Tyrosine Hydroxilase activity and PRL signaling during late pregnancy and early lactacion in rats

PENNACCHIO, GE; SOAJE M; SELTZER, AM; VALDEZ SR; ACOSTA C; JAHN GA

San Diego

Congreso; Society for Neuroscience 2016; 2016

Thyroid disorders compromise fertility in women of reproductive age and cause pregnancy disorders and lactation failure. Prolactin (PRL) is essential for female reproduction and has a leading role in the physiological adaptations that the maternal organism undergoes in order to achieve a successful pregnancy and lactation. The main regulator of PRL secretion is dopamine (DA), produced by the dopaminergic neurons located in the arcuate and periventricular hypothalamic nuclei. Previously we have shown that these patologies impair prolactin secretion during lactation and alter hypothalamic thyroid hormone receptors (TR) expression. To explore if hyperthyroidism affects PRL secretion through alterations of the hypothalamic dopaminergic systems, we studied the effect of T4 treatment on hypothalamic mRNA expression of Tyrosine hydroxylase (TOH, the rate-limiting enzyme for dopamine synthesis), PRL receptor (PRLR), members of the PRL signaling pathway (STAT, SOCS, CIS), in neuroendocrine dopaminergic neurons in medial basal hypothalamus (MBH) during late pregnancy and early lactation. Also we studied the protein expression of TOH, p-TOH, CIS and STAT5 in late pregnancy and early lactation. We also studied whether hypothalamic dopaminergic neurons express thyroid receptors by immunofluorescence (IF). Wistar control (Co: vehicle-treated) and hyperthyroid (HyperT: T4 sc, 250 µg/kg/day) rats were mated 8 days after the start of treatment and sacrificed at days 19 (G19), 20 (G20), 21 (G21) of pregnancy and day 2 of lactation. Total RNAs were extracted from MBH and the mRNA expression of PRL signalling pathway members was measured using real time PCR. Serum concentrations of PRL and THs were measured by RIA. In control rats, the mRNA expression of PRLR long, STAT5b, SOCS3, SOCS1 and CIS showed similar patterns of variations between late pregnancy and early lactation, with highest values in G19 and lower in G21, increasing again on L2. HyperT rats showed a similar pattern but PRLR and SOCS3 mRNAs were significantly increased on G19 and G20 respectively. STAT5 protein varied in parallel with changes in PRLR mRNA in both groups; the protein level decreased from G19 to G20 and remained low thereafter in controls while in the HyperT group values were significantly higher than controls in G19 and L2. CIS protein levels increased in controls at G20 and fell afterwards to levels similar to G19, while in the HyperT group CIS was significantly higher at G19 compared with controls and declined afterwards to values similar to controls. In controls, TOH mRNA and protein values diminished from G19 to G21 and remained low on L2. In HyperT rats TOH mRNA was similaar to controls on G19 and G20 but significantly higher on G21 and L2. HyperT decreased significantly TOH protein at G19 and G20. In control rats, p-TOH declined slowly from G20 to L2. HyperT increased significantly p-TOH on G19 and L2 compared with the controls. IF showed that TOH+ neurons also express TRβ, suggesting a possible direct action of THs on these neurons.Conclusion: the activity of hypothalamic dopaminergic neurons that regulate PRL secretion is affected by the excess of THs, resulting in increased PRL signaling and TOH activation on G19 and L2 and a decrease or no changes with respect to controls in G20 and G21. This pattern can be correlated with the advancement in the antepartum PRL peak followed by impaired PRL secretion during lactation previously observed in HyperT rats, that compromises the hyperprolactinemia necessary for a successful lactation.