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Hyperprolactinemia is a common clinical problem. Cases resulting from inappropriate prolactin secretion by the pituitary gland are the third most frequently diagnosed cause of chronic anovulation and secondary amenorrhea. There are many etiologies for this condition; some result from serious underlying pathology and others from reversible functional disorders.

Control of prolactin secretion is dominated by tonic inhibition and there is no regulation by classic negative feedback from its target organs. These characteristics are unique among pituitary hormones. The major inhibitor of prolactin secretion is dopamine and the two major stimuli are estrogen and thyrotropin-releasing hormone (TRH). Numerous other neurohormonal regulators must also be considered when elucidating the mechanisms by which hyperprolactinemia develops.

Hyperprolactinemia, Regulation of prolactin secretion, Physiologic hyperprolactinemia, Pharmacologic hyperprolactinemia, Pathologic hyperprolactinemia, Galactorrhea

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 pre- synthesized 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 deter- mined 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.

Physiologic hyperprolactinemia
Most physiologic hyperprolactinemia is transient and of no clinical consequence. High physiologic concentrations of plasma prolactin occur at night and result from both an intrinsic circadian rhythm and sleepentrained prolactin release. High protein meals at midday, but not in the morning, induce prolactin release through an unknown mechanism. Physical and emotional stress, including exercise, hypoglycemia and anesthesia are associated with elevations in prolactin secretion. Orgasm promotes prolactin secretion, but only in women. Pregnancy is associated with a marked elevation of prolactin secretion that persists into the immediate postpartum period (Chapter 23). Of all the physiologic hyperprolactinemic states, only lactation is associated with amenorrhea.

Pharmacologic hyperprolactinemia Medications that interfere with dopaminergic inhibition of the pituitary lactotroph can cause hyperprolactinemia. Any drug that decreases the synthesis of dopamine, enhances its metabolism, increases its reuptake or interferes with its binding to its receptor will reduce the action of dopamine. When the inhibitory activity of dopamine on the pituitary lactotroph is blocked, prolactin secretion increases. All of the medications listed in Table 32.1 can inhibit dopamine action and cause hyperprolactinemia. Clinical manifestations of pharmacologic hyperprolactinemia include galactorrhea and menstrual irregularities. Menstrual dysfunction may be severe enough to result in amenorrhea.

Pathologic hyperprolactinemia
Lesions in the hypothalamus or in the pituitary gland can cause hyperprolactinemia. Those in the hypothalamus typically do so by interfering with dopamine delivery to the pituitary gland. Tumors are the most frequent of the pituitary causes of hyperprolactinemia; the prolactin-secreting adenoma is the most common of these (Fig. 32.1b). Prolactin-secreting adenomas (prolactinomas) are classified by size: microadenomas are less than 1 cm in size and macroadenomas are greater than 1 cm. These tumors can occur in both men and women, but are more common in women. In women they cause galactorrhea, amenorrhea, headache and visual field defects. In men they cause headache, visual field changes and impotence. They are often larger at diagnosis in men than in women because symptom onset is typically late in men. Prolactinomas are usually benign. Pituitary adenomas that produce adrenocorticotropic hormone (Cushing disease) and growth hormone (acromegaly) may also cause hyperprolactinemia.
Primary hypothyroidism can also cause hyperprolactinemia. The decrease in circulating thyroid hormone that accompanies thyroid gland dysfunction diminishes negative feedback on the hypothalamus and pituitarygland.ThisresultsinanincreaseinTRHandthyroid-stimulating hormone secretion. Excessive TRH can override the normal dopamine dominated inhibition of prolactin secretion through direct, receptor- mediated effects on the pituitary lactotroph. A significant proportion of patients with chronic renal failure will have hyperprolactinemia. While the etiology of this effect remains incompletely described, patients with chronic renal failure appear to have circulating serum factors that interfere with dopaminergic inhibition of prolactin synthesis and secretion. Treatment of hyperprolactinemia is directed toward correction of the underlying cause. A notable exception to this rule involves the management of the prolactin-secreting pituitary adenoma. Resection of these tumors is associated with a high frequency of recurrence of the hyperprolactinemia. Medical management is typically safer and more effective and involves use of oral dopamine agonists (e.g., bromocriptine, cabergoline). It is important to remember that men and women with hyperprolactinemia are hypogonadal due to the associated abnormalities in the hypothalamic–pituitary–gonadal axis. This hypogonadal state places them at significant risk for osteoporosis (Chapter 24) and requires continuation of therapy for as long as the hyperprolactinemia persists.

Galactorrhea describes the secretion of breast milk in states unassociated with nursing. Galactorrhea can result from hyperprolactinemia or from excessive sensitivity of the breast to normal circulating levels of prolactin. If galactorrhea is associated with amenorrhea, then hyperprolactinemia is likely the cause. If galactorrhea occurs in the presence of normal ovulatory cycles, then excessive sensitivity of the breast to normal circulating amounts of prolactin is more likely. The three most common causes of hyperprolactinemia resulting in galactorrhea are: (i) a pituitary adenoma, (ii) medications interfering with dopamine action and (iii) hypothyroidism. Galactorrhea can be suppressed by the use of dopamine agonists.