Antipsychoticinduced Hyperprolactinemia
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Antipsychotic-Induced Hyperprolactinemia Jolene R. Bostwick, Pharm.D., Sally K. Guthrie, Pharm.D., FCCP,and Vicki L. Ellingrod, Pharm.D., FCCP Use of antipsychotic agents has been associated with hyperprolactinemia, or elevated prolactin levels; this hormonal abnormality can interfere with the functioning of reproductive, endocrine, and metabolic systems. As antipsychotic agents are increasingly used for both United States Food and Drug Administration–approved and nonapproved indications, many individuals are at risk for developing antipsychotic-induced hyperprolactinemia. First-generation antipsychotics pose the greatest risk of causing this adverse effect; however, second-generation antipsychotics, particularly risperidone and paliperidone, also often increase prolactin secretion. Hyperprolactinemia has short- and long-term consequences that can seriously affect quality of life: menstrual disturbances, galactorrhea, sexual dysfunction, gynecomastia, infertility, decreased bone mineral density, and breast cancer. Although many of these are definitively connected to elevated prolactin levels, some, such as breast cancer, require further study. Both clinicians and patients should be aware of hyperprolactinemia-associated effects. To prevent or alleviate the condition, tailoring an antipsychotic drug regimen to each individual patient is essential. In addition, the risk of hyperprolactinemia can be minimized by using the lowest effective dose of the antipsychotic agent. If the effects of prolactin are evident, the drug can be changed to another agent that is less likely to affect prolactin levels; alternatively, a dopamine agonist may be added, although this may compromise antipsychotic efficacy. Additional research is needed to clarify the appropriate level of monitoring, the long-term effects, and the optimal treatment of antipsychotic-induced hyperprolactinemia. Key Words: hyperprolactinemia, prolactin, antipsychotics, schizophrenia, osteoporosis, breast cancer, amenorrhea, sexual dysfunction. (Pharmacotherapy 2008;29(1):64–73) OUTLINE Use of antipsychotic agents has been associated Prolactin with hyperprolactinemia, or elevated prolactin Physiologic Effects of Hyperprolactinemia levels. Hyperprolactinemia is more than an Antipsychotic-Induced Hyperprolactinemia abnormal laboratory value; elevated prolactin Prevalence levels can interfere with the functioning of Consequences reproductive, endocrine, and metabolic systems. Antipsychotic Drug Selection and Management of the When first-generation antipsychotics were the Effects of Hyperprolactinemia only treatment available for psychosis, hyper- Conclusion prolactinemia from use of these agents was From the Department of Clinical, Social, and recognized but often ignored. All of the first- Administrative Sciences, University of Michigan College of generation antipsychotics caused hyperprolactinemia, Pharmacy, Ann Arbor, Michigan (all authors). and elevated prolactin levels were generally Address reprint requests to Jolene R. Bostwick, Pharm.D., accepted as both inevitable and preferable to BCPS, Department of Clinical, Social, and Administrative untreated psychosis. With the advent of atypical Sciences, University of Michigan College of Pharmacy, 1500 East Medical Center Drive, SPC 0118, Ann Arbor, MI 48109. or second-generation antipsychotics, clinical ANTIPSYCHOTIC-INDUCED HYPERPROLACTINEMIA Bostwick et al 65 monitoring and identification of the conse- particularly important for female patients with quences of hyperprolactinemia have received the A1 allele, who appear to be at an increased greater recognition because these agents can offer risk for developing antipsychotic-induced a differential profile of adverse effects and some hyperprolactinemia.5, 8 of the newer agents cause little to no elevation of Because of the complex regulation of prolactin prolactin levels. Recent research has provided a release, a variety of drugs have been associated with more comprehensive understanding of the many hyperprolactinemia, such as antidepressants (tri- functions of prolactin that result in the and tetracyclic antidepressants, monoamine oxidase multifactorial effects of hyperprolactinemia. inhibitors, serotonin-specific reuptake inhibitors), gastrointestinal drugs (metoclopramide, domperi- Prolactin done), antihypertensives (methyldopa, verapamil, reserpine), some serotonergic drugs, antiandrogens, Prolactin is a polypeptide hormone that estrogens, opiates, and cocaine.9, 10 Patients taking contains 199 amino acids and is categorized as 1 these drugs, particularly if used in combination with part of the growth hormone family. It is secreted antipsychotic agents, may be at an increased risk for primarily by lactotroph cells located in the drug-induced hyperprolactinemia. anterior pituitary. Prolactin also is produced in other locations such as adipose cells in subcu- Physiologic Effects of Hyperprolactinemia taneous, breast, and visceral tissues. Although the best known actions of prolactin relate to Any individual taking a drug that blocks the reproduction, pregnancy, and lactation, the inhibition of prolactin secretion is at risk for the hormone appears to be involved in many more development of hyperprolactinemia; however, functions than previously thought.2 Prolactin specific populations such as children, adolescents, binds to specific prolactin receptors that belong premenopausal women, and women in the to the class I cytokine receptor family and are perinatal period are at higher risk.1 During present in organs such as the pancreas, liver, pregnancy, the secretion of prolactin levels is uterus, and prostate.3 Binding at the prolactin elevated 10–20 times the nonpregnant value, receptor results in activation of a variety of resulting in breast enlargement and milk signaling pathways that alter the transcription of production, as well as decreases in libido and genes causing tissue changes.1, 2 fertility. Prolactin also affects actions of other Secretion of prolactin is pulsatile, with peaks hormones and enzymes in a variety of tissues. and troughs that follow a circadian cycle. Peak For instance, in hepatocytes, prolactin activates a secretion occurs nightly, approximately 4 hours cotransporting peptide for sodium-taurocholate; after sleep onset, and the nadir occurs in the in T lymphocytes, prolactin promotes production morning, approximately 6 hours after waking. In of interferon-regulatory factor 1; and in addition to circadian peaks, prolactin levels are reproductive tissue, it induces transcription of transiently elevated by meals, stress, and sexual the estrogen receptor and 3-hydroxysteroid activity. Regulation is complex, with serotonin dehydrogenase.3 Prolactin not only is produced (through 5-HT1A and 5-HT2 receptors) causing within adipose tissues but also may have a stimulation of prolactin release and estrogen regulatory function in the tissue, although that causing increased production of prolactin. However, exact function has not yet been determined. the major regulation of pituitary prolactin secretion Since prolactin has some of its strongest effects is largely inhibitory.4 Dopamine, which is released on the reproductive system, it is not surprising by tuberoinfundibular neurons, normally acts at that a supraphysiologic elevation of prolactin D2 receptors on lactotropes to tonically inhibit level should affect the reproductive organs. prolactin secretion and maintain physiologically Drug-induced hyperprolactinemia, resulting in normal prolactin levels in the blood. The Taq1 A elevations of prolactin level 2–4 times the upper polymorphism of the D2-receptor gene may play limit of the normal range of 15–25 µg/L in men a role in the strength of dopamine-mediated and women, causes significant effects on the inhibition of prolactin secretion. Carriers of the reproductive system. Elevated prolactin levels less frequent A1 allele have a lower density of D2 can affect sex hormone dysfunction by inhibiting receptors in the striatum, which can lead to a the release of hypothalamic gonadotropin- 11 dopamine deficiency through higher D2 releasing hormone. Once gonadotropin- occupancy, increasing the risk for antipsychotic- releasing hormone is inhibited, release of induced hyperprolactinemia.5–7 This may be luteinizing hormone and follicle-stimulating 66 PHARMACOTHERAPY Volume 29, Number 1, 2009 hormone from the pituitary is also inhibited. past. Although the second-generation anti- The inhibition of luteinizing hormone and psychotics do generally cause less anticholinergic follicle-stimulating hormone by elevated load and fewer extrapyramidal symptoms, they prolactin levels occurs in both men and women, may have a propensity to cause hyperglycemia, resulting in reduced testosterone and estrogen hyperlipidemia, and weight gain. In addition, the production that can lead to widespread landmark Clinical Antipsychotic Trials of Inter- consequences.12 vention Effectiveness (CATIE) study demonstrated Short-term concerns associated with hyper- that the efficacy of perphenazine (a first- prolactinemia include menstrual disturbances, generation antipsychotic) was comparable to that galactorrhea, sexual dysfunction, and infertility of many second-generation antipsychotics.24 The in women, as well as sexual dysfunction and burden of adverse events was also comparable, gynecomastia in men.1, 13 Galactorrhea can occur although the actual frequency of specific adverse in both sexes, but it is more common in women events differed among the antipsychotics and may occur in up to 57%