Has the mammary gland a protective mechanism against overexposure to triiodothyronine during the peripartum period? The prolactin pulse down-regulates mammary type I deiodinase responsiveness to norepinephrine

Abstract

Peripartum is a crucial period for mammary gland final differentiation and the onset of lactation. Although the 'trigger' for lactogenesis depends on several hormones, a key factor is the peripartum prolactin (PRL) pulse whose deletion results in a failure to initiate milk production. Other hormones having a critical role during this period but exerting a contrary effect are the thyronines. A transitory hypothyroidism occurs at peripartum in serum and several other extrathyroidal tissues, whereas the induction of hyperthyroidism during late pregnancy is associated with the absence of lactation after delivery. We analyzed the mammary gland during pregnancy and lactation for: (a) the type and amount of thyroid receptors (TRs), (b) the local triiodothyronine (T3) generation catalyzed by type I deiodinase (Dio1), (c) the Dio1 response to norepinephrine (NE) and (d) the effect on Dio1 and TRs of blocking the PRL pulse at peripartum. Our data showed that during pregnancy the mammary gland contains Dio1 in low amounts associated with the highest expression of TR 1; whereas during lactation the gland shows high levels of both Dio1 and TR 1. However, at peripartum, both TRs and Dio1 decrease, and Dio1 becomes refractory to NE. This refractoriness disappears when the PRL pulse is blocked by the dopamine agonist bromocriptine. This blockade is also accompanied by a significant decrease in cyclin D1 expression. Our data suggested that the peripartum PRL pulse is part of a protective mechanism against precocious differentiation and/or premature involution of the alveolar epithelium due to T3 overexposure.

Expression of nuclear hormone receptors, their coregulators and type I iodothyronine 5′-deiodinase gene in mammary tissue of nonlactating and postlactating rats

“…However, the expression level of TRh mRNA was of the same order in both normal nonlactating mammary gland and postlactating mammary tissue. These findings are in agreement with findings that TRa1 is expressed during the pubescent, pregnancy and weaning period and TRh1 is primarily expressed during lactation (Anguiano et al, 2004). TRh1 is associated with T 3 metabolic activity while TRa1 plays important role in cell differentiation and apoptosis effects (Yen, 2001).…”

“…4). This finding is also in agreement with activity of 5V-DI during breeding cycle and expression pattern of TRh1 (Anguiano et al, 2004).…”

Effect of hypothyroidism on the expression of nuclear receptors and their co-regulators in mammary gland during lactation in the rat

“…In this hormonal condition, TH binding to TRα1 could repress TRα2 and TRβ1 transcription in response to negative autoregulation similar to that observed in GH1 cells (Samuels et al, 1977). The low values, relative to L7, of TRα2 and TRβ1 mRNA and protein observed at L2 support the hypothesis of a protective mechanism raised by Anguiano et al (2004). These authors proposed that in the peripartum the mammary gland is protected against deleterious actions of TH such as inducing premature involution (Varas et al, 2002) or blocking PRL-induced STAT5 activation (Favre-Young et al, 2000).…”

“…In addition to the changes in circulating THs, during early post-partum and lactation PRL finely tunes mammary Dio1 expression and activity, providing the optimal T3 concentrations Anguiano et al, 2004). Another potential regulatory point is differential expression of the TR isoforms expressed in mammary tissue.…”

“…It has been demonstrated that triiodothyronine (T3) antagonizes PRL signaling through inhibition of signal transducer and activator of transcription 5 a (STAT5a) mediated transcriptional activity (one key component of PRL signaling pathway) (Favre-Young et al, 2000). Highlighting the necessity of exposure of the mammary tissue to precise TH concentrations, it has been shown that PRL regulates mammary deiodinase 1 (Dio1) and TH receptors (TR) α1 and β1 expression during the transition from pregnancy to lactation as well as in established lactation Anguiano et al, 2004).…”