Regulation of prolactin secretion

Embryonic differentiation of the lactotroph is under the control of the pituitary-specific transcriptional factor Pit-1. While Pit-1 regulates prolactin gene transcription by binding directly to the prolactin promoter, other regulators of prolactin gene expression use alternative pathways (Fig. 32.1a). Dopamine released into the pituitary portal system binds to a G₁-protein-coupled receptor and inhibits adenylate cyclase and phospholipase C. Acting as a neurohormone, rather than a neurotransmitter, dopamine reduces prolactin synthesis and prolactin release by the pituitary lactotrope. TRH acts through a second lactotroph cell membrane receptor to activate phospholipase C. In contrast to dopamine, TRH increases prolactin gene transcription and release of prolactin hormone from its storage granules. The effect of TRH is modulated by thyroid hormone such that decreases in T₃ and T₄ enhance prolactin release and increased concentrations of T₃ and T₄ decrease prolactin secretion. Estradiol acts through a third mechanism, binding not to a membrane receptor but to a nuclear receptor. The hormone receptor complex then interacts with estrogen response elements upstream of the prolactin gene. Estradiol also interferes with dopaminergic activation of its receptor and increases the concentration of TRH receptors on lactotrophs. Both actions potentiate the stimulatory effects of the sex steroid.

Like dopamine, γ-aminobutyric acid (GABA) and glucocorticoids inhibit prolactin secretion. The mechanism by which GABA acts as a prolactin inhibitory factor is unknown. Like estrogen, glucocorticoids act through nuclear receptors to inhibit prolactin gene transcription. Vasoactive peptide (VIP), oxytocin, angiotensin II (AgII) and serotonin all increase prolactin secretion. VIP employs two mechanisms: it stimulates oxytocin release via the hypothalamus and it interferes with dopamine inhibition of adenylate cyclase. AgII acts on a specific membrane receptor on the lactotroph to provoke rapid release of presynthesized prolactin. It is a more potent secretagogue for prolactin than TRH. Serotonin released by the dorsal raphe nucleus also stimulates prolactin release but not its synthesis. Here, serotonin activity occurs independent of dopamine pathways.

In the physiologic state, fine tuning of prolactin secretion is determined by the balance between the prolactin inhibitory factors (PIF) and the prolactin-releasing factors (PRF). Any disorder that alters the balanced secretion of these regulatory compounds will result in altered prolactin secretion. Regardless of its cause, hyperprolactinemia can interfere with hypothalamic–pituitary function and result in hypogonadism with or without galactorrhea. The fact that women with prolactin-induced amenorrhea are hypo-estrogenic but do not experience hot flashes suggests that one mechanism by which prolactin alters hypothalamic–pituitary function is via modulation of central neurotransmission. The hypothalamic dopaminergic and opioid systems that regulate gonadotropin-releasing hormone (GnRH) pulsatility are likely to be involved in this effect.