In contrast to other anterior pituitary hormones, which are controlled by hypothalamic-releasing factors, prolactin secretion is primarily under inhibitory control mediated by dopamine. Multiple lines of evidence suggest that dopamine, which is secreted by the tuberoinfundibular dopaminergic neurons into the portal hypophyseal vessels, is the primary prolactininhibiting factor. Dopamine receptors were found on pituitary lactotrophs, and treatment with dopamine or dopamine agonists suppresses prolactin secretion (242–248). The dopamine antagonist metoclopramide abolishes the pulsatility of prolactin release and increases serum prolactin levels (244,245,249). Interference with dopamine transit from the hypothalamus to the pituitary by mass lesions, or blockade of the dopamine receptor as occurs with antipsychotic and other medications, increases serum prolactin levels. Thyrotropin-releasing hormone (TRH) causes prolactin release when present at supraphysiologic levels (as in primary hypothyroidism), but does not appear to play an important modulatory role in the normal physiologic regulation of prolactin secretion. γ -Aminobutyric acid (GABA) and other neurohormones and neurotransmitters may function as prolactin-inhibiting factors (250–253). Several hypothalamic polypeptides that modulate prolactin-releasing activity are listed in Table 31.9. It appears that dopamine and
Table 31.9 Chemical Factors Modulating Prolactin Release and Conditions that Result in Hyperprolactinemia
Major surgery and disorders of chest wall (burns, herpes, chest percussion)
Postpartum (nonnursing: days 1–7; nursing: with suckling)
Table 31.9 Continued
Metastatic tumors (especially of the lungs and breasts)
Trauma to stalk
Ectopic production (hypernephroma, bronchogenic sarcoma)
Antidepressants (amoxapine, imipramine, amitriptyline)
Dopamine antagonists (phenothiazines, thioxanthenes, butyrophenone, diphenylbutylpiperidine, dibenzoxazepine, dihydroindolone, procainamide, metoclopramide)
TRH act as primary neurohormones, while others (i.e., neuropeptide Y, galanin, and enkephalin) act as modulators. It is likely that under differing physiologic conditions (i.e., pregnancy, lactation, stress, aging) a modulator may become a principal regulator of hormone secretion.
The prolactin receptor is a member of the class 1 cytokine receptor superfamily and is encoded by a gene on chromosome 5 (254). Transcriptional regulation of the prolactin receptor is accomplished through three tissue-specific promoter regions; promoter I for the gonads, promoter II for the liver, and promoter III, a generic promoter that includes the mammary gland (255).
Hyperprolactinemia Physiologic disturbances, pharmacologic agents, or markedly compromised renal function may cause elevations in prolactin levels, and transient elevations occur with acute stress or painful stimuli. The most common cause of elevated prolactin levels is likely pharmacologic; most patients using antipsychotic medications and many other patients using agents with antidopaminergic properties will exhibit moderately elevated prolactin levels. Drug-related and physiologic conditions resulting in hyperprolactinemia do not always require direct intervention to normalize prolactin levels.