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

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

California

Congreso; 46th Annual Meeting of Society for Neuroscience. San Diego, CA; 2016

Society for Neuroscience

Abstract:Thyroid disorders compromise fertility in women of reproductive age and causepregnancydisorders and lactation failure. Prolactin (PRL) is essential for femalereproduction.The mainregulator of PRL secretion is dopamine, produced by the dopaminergic neuronslocated inthe medial basal hypothalamus (MBH). To explore if hyperthyroidism affects PRLsecretionthrough alterations of the hypothalamic dopaminergic systems, we studied theeffect ofT4treatment on hypothalamic expression of Tyrosine hydroxylase (TOH, therate-limitingenzyme fordopamine synthesis), PRL receptor (PRLR), members of the PRL signaling pathway(STAT,SOCS, CIS), in MBH during late pregnancy and early lactation. We also studiedthisneuronsexpress thyroid receptors by immunofluorescence (IF). Wistar control (Co:vehicletreated)andhyperthyroid (HyperT: T4 sc, 250 μg/kg/day) rats were mated 8 days after the startoftreatment and sacrificed at days 19 (G19), 20 (G20), 21 (G21) of pregnancy andday 2 oflactation.Total RNAs were extracted from MBH and the mRNA expression was measured usingreal timePCR. In control rats, the mRNA expression of PRLR long, STAT5b, SOCS3, SOCS1and CISshowed similar patterns of variations between late pregnancy and earlylactation.HyperT ratsshowed a similar pattern but PRLR and SOCS3 mRNAs. STAT5 protein varied inparallelwith changes in PRLR mRNA in both groups; the protein level decreased from G19toG20 andremained low thereafter in controls while in the HyperT group values weresignificantlyhigher thancontrols in G19 and L2. CIS protein levels increased in controls at G20 andfellafterwardsto levels similar to G19, while in the HyperT group CIS was significantly higheratG19compared with controls and declined afterwards to values similar to controls.Incontrols,TOHmRNA and protein values diminished from G19 to G21 and remained low on L2.In HyperTrats TOH mRNA was similaar to controls on G19 and G20 but significantly higheronG21 and L2.HyperT decreased significantly TOH protein at G19 and G20. In control rats, p-TOHdeclined slowly from G20 to L2. HyperT increased significantly p-TOH on G19 andL2comparedwith the controls. IF showed that TOH+ neurons also express TRβ, suggesting apossibledirect action of THs on these neurons. Conclusion: the activity of hypothalamicneuronsthatregulate PRL secretion is affected by the HyperT, resulting in increased PRLsignaling andTOHactivation on G19 and L2. This pattern can be correlated with the advancementin theantepartumPRL peak followed by impaired PRL secretion during lactation previouslyobservedin HyperTrats, that compromises the hyperprolactinemia necessary for a successfullactation.