Regulation Of Circulating Prolactin Concentrations and Lactogenesis

Introduction
Endocrine systems play a crucial role in the homeostatic control of physiological processes in the human body. In a process called neuroendocrine integration, the nervous and endocrine systems interact to allow the regulation of physiological pathways. Neuroendocrine processes show commonalities in the ways they are controlled and in the mechanisms by which they exert their function. However, numerous studies have contributed to identifying a striking exception: Pituitary prolactin shows significant discrepancies from the idiosyncratic characteristics of the other pituitary hormones. This essay aims to scrutinize the regulation of prolactin levels and to outline changes in prolactin regulation occurring in late pregnancy. The subject of this essay is also the identification of specific details concerning prolactin regulation, where there is not enough evidence to allow a reliable conclusion.

Anatomy and physiology of the pituitary gland
The pituitary gland, also known as the hypophysial gland, is located in the hypophysial fossa and consists of three components: The adenohypophysis is of fundamental importance for the functional and homeostatic regulation of neuroendocrine-controlled processes. The intermediate lobe synthesizes and secretes melanotropins and trigger the release of melanin via melanocortin receptors. The third part, which is posterior to the intermediate lobe is known
as neurohypophysis and is linked to the hypothalamus by the median eminence, a part of the hypothalamus where regulatory hormones are released (Melmed S. 2011). Hypophysial hormones affect blood pressure and energy utilization, reproduction, osmoregulation, metabolism and many more physiological processes. The secretion of most pituitary hormones is tightly controlled by hypothalamic factors that are released into the hypothalamohypophysial portal system at the median eminence. This blood
vessel system carries the factors that are produced by parvocellular neurosecretory cells in the hypothalamus to the anterior pituitary gland where they exert their effects on hormone release from adeno-hypophysial endocrine cells.

Together, the adeno-hypophysial gland and the hypothalamus form the hypothalamo-pituitary-axis, one of the most complex endocrine systems in the human body. The hypothalamic regulatory hormones are released into the portal system following appropriate stimulation from upper cortical regions. This input can be evoked by environmental cues such as temperature, light, olfactory stimuli, etc., or internal triggers such as peripheral endocrine feedback. Once these specific signals are transmitted to the hypothalamus, it coordinates the release of appropriate regulatory hormones which reach the secretory endocrine cells of the anterior the pituitary in high concentrations and either upregulate or downregulate the release of hormones there, depending on the specific character of the regulatory elements in the feedback system. The hormones are then released into the systemic circulation and ideally reach their target tissues which are usually peripheral endocrine glands. These endocrine targets release further hormones that constitute a part of the neuroendocrine regulatory feedback system, thus up or downregulate the secretion of pituitary hormones through hypothalamic mediation.

Prolactin: An exceptional pituitary hormone
Prolactin, however, is pleiotropic and affects a wide range of tissues and does not necessarily affect only endocrine target tissue. Therefore, it cannot make use of the classical feedback system which makes use of peripheral hormone feedback and instead employs a short feedback loop to control its own secretion. In experiments on rats, ‘pseudopregnancy’, thus, elevated prolactin levels could be observed, when drugs were applied which lead to a reduction of catecholamines (Barraclough & Sawyer, 1959) suggesting that catecholamines such as dopamine must be involved in the control of prolactin secretion (Mcleod at al., 1970). The findings from applying exogenous, dopaminergic agonists supported this hypothesis, as they displayed increased prolactin suppression. Molecular investigations confirmed the presence of dopaminergic D2 receptors in the adenohypophysis. Dopamine, thus, seems to inhibit prolactin secretion in the anterior pituitary gland. Dopaminergic neurons in the arcuate nucleus are activated when stimulated with prolactin. This indicates that prolactin inhibits its own release by acting upon inhibitory dopaminergic neurons. This theory is empirically supported by observations of basal prolactin secretion from endocrine cells in the anterior lobe of the pituitary gland (Gregerson KA., 2006). When activated by prolactin on the D2 receptors, the electrophysiological response of dopaminergic neurons prevents Ca2+ influx into neurosecretory cells at the anterior lobe. The consequent hyperpolarization results in a decreased vesicular release of prolactin. Therefore, it can be concluded, that prolactin exerts and inhibitory control of its levels through its action on hypothalamic dopamine-releasing
neurons, also known as tuberoinfundibular dopamine neurons (TIDA neurons).

Adaptive plasticity during pregnancy
This balance is disrupted during pregnancy when hyperlacticaemia is required for lactation. The plasticity of the prolactin feedback system is crucial to promote milk production. This happens in the late phase of pregnancy. Until then, the regular, inhibitory feedback system is predominantly active. In the first months of pregnancy, placental lactogens mimic prolactin and act on its receptors ensuring continued activity of dopaminergic neurons, keeping prolactin levels low. The major adaptions happen in late pregnancy when dopamine neurons do not seem to respond to placental lactogens nor prolactin anymore (Andrews et al., 2001). This decrease in dopaminergic activity consequently leads to a rise in prolactin levels which is maintained during lactation. High levels of prolactin are required for maternal behaviour as well as for lactation at this stage. The levels of prolactin are unaffected by the inhibitory short loop feedback systems. It is important to note that the bypassing of the inhibitory feedback loop is not due to a decrease in expression of dopaminergic receptors on hypothalamic neurons, but rather due to a modified cellular response following activation of dopamine
receptors. Adaptations at the cellular level lead to a decreased synthesis of dopamine (Feher et al., 2010) which is accompanied by higher levels of enkephalin expression in dopaminergic neurons. Prolactin secretion is induced by a suckling stimulus at the mammary duct which supposedly leads to a decrease in dopamine synthesis in the neurons of the median eminence
(Selmanoff & Wise, 1981). However, to a certain extent, this is inconsistent with the model of chronically low levels of dopamine during the period of lactation.

Figure 1: Visual representation of core elements in the prolactin regulation pathway comprising input signals and feedback systems as well as a diagrammatic outline of hypothalamic-pituitary anatomy (Wilkinson, 2019).

Uncertainties in prolactin regulation
It is not entirely clear how suckling can lead to prolactin secretion through dopamine withdrawal if dopamine levels are low anyway during this period. Some research indicates that there might be another ‘prolactin-releasing factor’ that could trigger prolactin release. However, this factor has not been identified so far. Several hormones such as oxytocin, angiotensin, vasopressin, TRH, galanin etc. have exhibited controlling activities on prolactin secretion (Schlomo M., Ben-Schlomo A., 2017). Estradiol, for example, an ovarian steroid, exerts its control of prolactin secretion principally in three ways. It upregulates gene expression of prolactin (Lieberman et al. 1981), promotes the synthesis of lactotroph cells (Kansra et al., 2005) and their sensitivity to prolactin and other regulators (West & Dannies 1980). It has also shown to indirectly decrease the concentration of dopamine in the hypothalamic-hypophysial portal system (Cramer et al., 1979), thus enhancing the secretion of prolactin. The diverse mode of action of estradiol concerning the control of prolactin is also emphasized by its ability to change the number of prolactin receptors on neurons (Lerant & Freeman, 1998).

However, neither estradiol nor the other mentioned hormones are classical hypothalamic factors with prolactin-specificity that are released into the portal blood system at the median eminence ergo cannot be defined as prolactin-specific releasing factors. As briefly mentioned above, simultaneously to the decline of dopamine, enkephalins levels in dopamine-releasing neurons have shown to rise and respond to stimulation by prolactin (Merchenthaler 1993). Enkephalins could, therefore, be the factor researchers are looking for. However, the exact process by which this would happen as well as other functions of enkephalins are still unclear
to date. Further research also indicates that there could be an uninterrupted neuronal connection from the mammary gland to the hypothalamus where somatosensory input could be translated into modified regulation of prolactin release (Berghorn et al., 2001). The suckling would thus stimulate a neuronal pathway and directly affect prolactin secretion. At this stage, another pituitary hormone plays an important role. Oxytocin is released in response to the suckling and stimulates contraction of myoepithelial cells around milk containing alveoli and thus finalizes the process of lactation.
Experiments in which the pituitary stalk was cut or hypophysectomy was performed on rats showed that prolactin secretion was maintained, even when the neural connection between the hypothalamus and pituitary was surgically removed. However, the amounts of prolactin and with that the extent of lactation significantly changed. This suggests, that the hypothalamus is very important for the regulation of prolactin secretion but that the secretion per se is independent of neural stimuli and hypothalamic factors that researchers are currently looking for.

Conclusion
The regulation of prolactin by other pituitary hormones underlies a complex network of control systems and feedback loops. Prolactin exhibits characteristics that are particularly versatile and unique amongst adeno-hypophysial hormones. Its feedback system displays strong adaptive plasticity to enable lactation, however, the exact process is subject to intense scientific scrutiny as a prolactin-releasing factor has yet to be identified to gain a better
understanding of the lactation process.

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