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Hyperprolactinemia—increased levels of prolactin (PRL) in the blood that may be caused by hypothyroidism, pituitary disorders, atypical antipsychotics, or other conditions and medications—has numerous physiologic manifestations, including amenorrhea, infertility, abnormal bone resorption, increased risk of breast cancer, and compromised immunity. Evaluation of hyperprolactinemia in patients taking psychotropics—particularly children and adolescents, in whom hyperprolactinemia’s adverse effects may be more pronounced—should include an examination for signs and symptoms of hyperprolactinemia and assessment to rule out other potential causes. This article reviews hyperprolactinemia’s causes, symptoms, evaluation, and treatment, with an emphasis on younger patients.
Causes of hyperprolactinemia
PRL is a circulating autocrine or paracrine factor (Box 1).1,2 Its primary biologic activities can be broadly divided into 4 areas: reproductive, metabolic, osmoregulatory, and immunoregulatory (Box 2).1,3-8
Hyperprolactinemia has numerous physiologic and iatrogenic causes (Table 1).9 Substantially increased serum PRL levels may be seen with:
- prolactinomas, which usually present as incidental findings on a brain CT or MRI or with symptoms of tumor mass
- a craniopharyngioma or other tumor that compresses the pituitary stalk or hypothalamus and interrupts the hypothalamic-dopa minergic inhibition of PRL release.10
Primary thyroid failure (hypothyroidism) can produce a compensatory increase in the discharge of central hypothalamic thyrotropin-releasing hormone, resulting in increased stimulation of PRL secretion.10
Medications can increase serum PRL (Table 2)9 and cause clinical symptoms similar to those of physiologically induced hyperprolactinemia.
Conventional antipsychotics. The anti-psychotic potency of phenothiazines, thioxanthenes, butyrophenones, and dibenzoxazepines generally parallels their potency in increasing PRL levels.9 Although a dose-response relationship between PRL concentrations and conventional antipsychotics is likely, immediate and pronounced increases in PRL can occur even with low doses.
Prospective studies have shown that 3 to 9 weeks of treatment with an antipsychotic such as chlorpromazine increased mean baseline PRL levels up to 10-fold, even at therapeutic doses.11 Conventional antipsychotics can cause marked increases in PRL, probably by blocking dopamine receptors in the tuberoinfundibular tract.12 The blockage of D2 receptors removes the main inhibitory influence on PRL secretion and is associated with increased PRL release.12
Atypical antipsychotics cause less elevation in PRL levels than conventional anti-psychotics. This may be because of their:
- highly selective mesolimbic and meso-cortical dopamine receptor antagonism, which spares dopamine blockade within the tuberoinfundibular tract
- relatively lower D2 receptor affinity.11
Risperidone and its active metabolite paliperidone (9-hydroxyrisperidone) have a high affinity for D2 receptors and thus have potent D2 antagonistic effects.12,13 At dosages of 8 mg/d to 11.8 mg/d, risperidone and paliperidone are associated with the greatest increase in PRL levels among atypical antipsychotics.14
The rate of risperidone metabolism depends on the patient’s cytochrome P (CYP) 2D6 liver enzyme genotype. “Extensive” CYP2D6 metabolizers convert risperidone rapidly into 9-hydroxyrisperidone, whereas “poor” CYP2D6 metabolizers convert it much more slowly. Six percent to 8% of white individuals and a very low percentage of Asians have little or no CYP2D6 activity and are “poor metabolizers.” CYP2D6 also is inhibited by various substrates and nonsubstrates, notably quinidine. Although extensive metabolizers have lower risperidone and higher 9-hydroxyrisperidone concentrations than poor metabolizers, the pharmacokinetics of the active moiety after single and multiple doses are similar in extensive and poor metabolizers.15
Clozapine, olanzapine, quetiapine, ziprasidone, and aripiprazole are associated with a much lower risk of PRL elevation than risperidone. In an 8-week open-label trial, aripiprazole (mean dose 9.4±4.2 mg/d), did not increase serum PRL in 15 children and adolescents.2
Ziprasidone may cause only transient PRL elevation.16 PRL abnormalities may be least likely with clozapine and quetiapine, possibly because of their relatively lower D2 receptor affinity. Amenorrhea, galactorrhea, or inhibition of ejaculation have not been reported with the use of these 2 antipsychotics.16 Patients who developed hyperprolactinemia on conventional anti-psychotics have been treated subsequently with clozapine without hyperprolactinemia recurrence.16 Iloperidone has been associated with decreased PRL levels.17
Antidepressants that work by blocking catecholamine reuptake also cause hyperprolactinemia. This increase may be related to the antidopaminergic, stimulatory effects of estrogen. Numerous cases of galactorrhea and amenorrhea have been reported with the use of selective serotonin reuptake inhibitors (SSRIs).16 Galactorrhea has been reported in women who took venlafaxine.12 Less is known about the effects of nefazodone or bupropion on serum PRL. Mirtazapine can decrease serum PRL in men, probably through indirect 5-HT1 agonist and 5-HT2 and 5-HT3 antagonist activity.16