Under normal circumstances, prolactin regulates its own release via a short-loop negative feedback mechanism in which prolactin, secreted from lactotrophs situated within the anterior pituitary gland, stimulates dopaminergic neurons in the hypothalamus to release dopamine into portal blood circulation. Dopamine, in turn, inhibits lactotroph activity. A change in this regulation of prolactin secretion is seen during late pregnancy where tuberoinfundibular dopaminergic (TIDA) neurons no longer respond to elevated levels of placental lactogen (PL), a lactogen structurally and functionally similar to prolactin, allowing a prolonged elevation of prolactin secretion and the induction of an antepartum prolactin surge (Andrews et al., 2001). The mechanisms behind this loss of responsiveness have not yet been determined.
Prolactin acts by binding to its receptor on TIDA neurons and activating the signal transducer and activator of transcription 5b (STAT5b). During lactation, prolactin-induced activation of STAT5b is suppressed. This reduction in STAT5b signalling is consistent with a loss in TIDA responsiveness and is correlated with an increase in suppressor of cytokine signalling (SOCS) messenger ribonucleic acid (mRNA) expression within the arcuate nucleus. As SOCS proteins are known to disrupt prolactin signalling by interfering with STAT signalling in other systems, it is likely that the change in TIDA responsiveness to prolactin or PL during late pregnancy occurs at least partially in response to an increase in SOCS proteins at this time. Although prolactin can induce SOCS mRNA expression within the arcuate nucleus, the level of SOCS mRNA expression observed on day 20 of pregnancy is significantly lower to that observed on day 22. As PL is elevated on day 20 of pregnancy, some other factor or a combination of factors unique to the final 2 days of pregnancy induces the change in prolactin signalling. Late pregnancy is associated with elevated levels of estrogen while progesterone significantly declines. The aim of this study was to test the hypothesis that a fall in progesterone in the presence of elevated levels of estrogen during late pregnancy induces the increase in SOCS levels within TIDA neurons. This then results in a disruption of prolactin signalling, a decline in dopamine production and release, and the induction of the antepartum prolactin surge.
To determine if ovarian steroid hormones can act directly on TIDA neurons during late pregnancy, expression of progesterone receptors (PR) and estrogen receptors (ER) within TIDA neurons were examined during pregnancy and lactation. Using double-labelled immunohistochemistry, expression of both steroid receptors within arcuate dopaminergic neurons during pregnancy and lactation was confirmed. This is consistent with the hypothesis that changing levels of steroid hormones might directly regulate TIDA activity. Furthermore, as the level of steroid receptor expression within TIDA neurons did not change significantly during pregnancy and lactation, it is likely that changing levels of serum estrogen and progesterone may affect these neurons at this time.
To investigate the potential effects of steroid hormones on prolactin-induced and non prolactin-induced expression of SOCS mRNA, ovariectomised rats were treated with bromocriptine to suppress endogenous prolactin, and were then treated with a regime of chronic progesterone and/or estrogen in the presence and absence of an induced prolactin surge. SOCS mRNA expression within the arcuate nucleus was measured using real time quantitative RT-PCR. It was found that both estrogen and prolactin independently induced SOCS mRNA expression within the arcuate nucleus, but high levels of progesterone inhibited this effect. This supported the hypothesis that a change in SOCS mRNA expression within TIDA neurons might occur following the changes in steroid hormone levels observed during late pregnancy.
To specifically investigate the role of estrogen and progesterone in regulating SOCS expression during late pregnancy, an animal model was designed to experimentally alter estrogen and progesterone levels during late pregnancy, and then SOCS mRNA expression was examined. In this model, advancing the late pregnant decline in progesterone resulted in a significant advance in the timing of the antepartum prolactin surge and parturition, while delaying the decline in progesterone abolished the antepartum prolactin surge and delayed parturition. Furthermore, within this model, elevated levels of SOCS mRNA expression were always observed following the withdrawal of progesterone. This suggested that following the decline in progesterone during late pregnancy, elevated levels of estrogen (or PL) are able to induce SOCS mRNA expression within the arcuate nucleus. Given that SOCS proteins disrupt cytokine signalling in other systems, the induction of SOCS proteins during late pregnancy would then presumably mediate the change in TIDA responsiveness to prolactin.
To determine whether it was possible to change prolactin responses without affecting parturition, it was hoped to specifically alter progesterone and estrogen signalling in the brain. This was done by centrally administering progesterone to maintain progesterone levels during late pregnancy, and the ER antagonist ICI-182,780 (ICI) to block central estrogen levels. To determine the effectiveness of intracerebroventricular (icv) administration of ICI, two central estrogen mediated endpoints were evaluated: estrogen negative feedback on gonadotrophin releasing hormone (GnRH) pulse frequency (as measured by the frequency luteinizing hormone (LH) pulses) and the induction of PR within hypothalamic nuclei. Also, to confirm that central administration of ICI did not have a peripheral effect, estrogen induced uterine proliferation was measured. Although central ICI administration at the maximum possible dose affected estrogen-induced GnRH pulse frequency and partially reduced estrogen-induced PR expression within arcuate dopaminergic neurons, ICI did not affect the antepartum prolactin surge. Furthermore, cental administration of progesterone did not abolish the antepartum prolactin surge. This suggested that central administration of ICI and progesterone as a tool for researching central actions of ovarian steroids is likely to be limited to certain central endpoints, and was not suitable as a model to study central steroid effects on prolactin regulation.
Overall, the progression of the findings in this study led to the formulation of a key hypothesis: that during late pregnancy, elevated levels of estrogen and the withdrawal of progesterone allows for the prolactin-induced increase of SOCS proteins within TIDA neurons. Elevated levels of SOCS proteins may then disrupt normal prolactin signalling, mediated via the JAK/STAT pathway. This results in reduced dopamine synthesis and release and, the subsequent induction of the antepartum prolactin surge.
| Identifer | oai:union.ndltd.org:ADTP/217759 |
| Date | January 2007 |
| Creators | Steyn, Frederik Jacobus, n/a |
| Publisher | University of Otago. Department of Anatomy & Structural Biology |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | http://policy01.otago.ac.nz/policies/FMPro?-db=policies.fm&-format=viewpolicy.html&-lay=viewpolicy&-sortfield=Title&Type=Academic&-recid=33025&-find), Copyright Frederik Jacobus Steyn |
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