Abstract
Hyperprolactinemia is a common endocrinological disorder that may be caused by several physiological and pathological conditions. Several drugs may determine a significant increase in prolactin serum concentration that is frequently associated with symptoms. The so-called typical antipsychotics are frequently responsible for drug-related hyperprolactinemia. Risperidone is one of the atypical neuroleptics most likely to induce hyperprolactinemia, while other atypical drugs are unfrequenlty and only transiently associated with increase of prolactin levels. Women are more sensitive than men to the hyperprolactinemic effect of antipsychotics. Classical and risperidone-induced hyperprolactinemia may be revert when a gradual antipsychotic drug discontinuation is combined with olanzapine or clozapine initiation. Antidepressant drugs with serotoninergic activity, including selective serotonin reuptake inhibitors (SSRI), monoamine oxidase inhibitors (MAO-I) and some tricyclics, can cause hyperprolactinemia. A long list of other compounds may determine an increase in prolactin levels, including prokinetics, opiates, estrogens, anti-androgens, anti-hypertensive drugs, H2-receptor antagonists, anti-convulsivants and cholinomimetics. Finally, hyperprolactinemia has also been documented during conditioning and after autologous blood stem-cell transplantation and during chemotherapy, even though disturbances of prolactin seem to occur less frequently than impairments of the hypothalamus-pituitary-gonad/thyroid axis after intensive treatment and blood marrow transplantation.
Keywords: anti-depressants, anti-psychotics, estrogens, opioids, prokinetics, prolactin
Prolactin (PRL) is a 23 kDa polypeptide hormone secreted by the lactotroph cells of the anterior pituitary gland. It is released with a circadian trend, in 4 to 14 daily secretory pulses of increasing amplitude after sleep onset, with a decline short after waking and nadir around noon. Prolactin secretion responds to physiological stimuli: it increases after food intake and breast mechanical stimulation. Prolactin main biological role is milk induction and lactation, but it probably exerts also metabolic effects and takes part in reproductive mammary development, parental behavior (Benker et al 1990) and immune responsiveness stimulation (Halbreich et al 2003).
Even though monomeric 23 kDa form is predominant, big variants of 50 kDa and prolactin-IgG complexes of 150 kDa, with high immunogenic properties but poor biological effects, can circulate in large amount (up to 85% of total prolactin). This condition, referred to as macroprolactinemia, is characterized by normal levels of biological prolactin and lack of clinical symptoms (Gibney et al 2005).
Accurate definition of normal prolactin serum concentration can be difficult, because of high inter-individual variability and the frequent occurrence of macroprolactinemia, that can be revealed by polyethylene glycol precipitation of serum samples (Suliman et al 2003).
Prolactin homeostasis is the result of a complex balance between positive and negative stimuli, derivating from both external and endogenous environment. A plenty of mediators, of central, pituitary and peripheral origin (Freeman et al 2000, ), take part in regulating prolactin secretion, through a direct or indirect effect on lactotroph cells.
Major agents regulating prolactin secretion.
The main physiologic control of prolactin secretion is exerted by the inhibiting action of dopamine. Dopamine, secreted in hypothalamic periventricular zone (periventricular nucleus and arcuates nucleus) and released from neuronal projections in the median eminence, reaches the anterior pituitary gland through portal vessels (system known as tuberoinfundibular dopamine pathway or TIDA). The dopamine-mediated inhibition of prolactin secretion occurs through the binding of D2 receptors on the membrane of lactotroph cells and involves several signal transduction systems, resulting in inhibition of prolactin gene transcription, reduction of prolactin synthesis and release.
Other prolactin inhibiting factors of CNS derivation include GABA, somatostatin, acetylcholine and norepinephine; an autocrine regulation is exerted by prolactin through a short loop negative feedback on its own release, by stimulating TIDA cells through prolactin receptors binding, while GH, TGF1 and endothelin have a paracrine regulating role at pituitary level.
Excerpt from:
Pharmacological causes of hyperprolactinemia