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Minimizing the impact of elevated in children and adolescents

Early identification, treatment can help lessen impaired development, other sequelae

yperprolactinemia—increased levels of prolac- tin (PRL) in the that may be caused by Hhypothyroidism, pituitary disorders, atypical , or other conditions and medications— has numerous physiologic manifestations, including , , abnormal bone resorption, increased risk of cancer, and compromised im- munity. Evaluation of hyperprolactinemia in patients taking psychotropics—particularly children and ado- lescents, in whom hyperprolactinemia’s adverse effects may be more pronounced—should include an exami- nation for signs and symptoms of hyperprolactinemia and assessment to rule out other potential causes. This article reviews hyperprolactinemia’s causes, symp- toms, evaluation, and treatment, with an emphasis on © PHOTOS.COM younger patients. Wynn W. Paing, MD Private Practice, and Adolescent Psychiatry Causes of hyperprolactinemia Elkins Park, PA PRL is a circulating autocrine or paracrine factor (Box 1, Ronald A. Weller, MD Lecturer, Department of Psychiatry 1,2 page 48). Its primary biologic activities can be broadly University of Pennsylvania divided into 4 areas: reproductive, metabolic, osmo- Philadelphia, PA regulatory, and immunoregulatory (Box 2, page 49).1,3-8 Roomana Sheikh, MD Hyperprolactinemia has numerous physiologic and Clinical Assistant Professor of Psychiatry iatrogenic causes (Table 1, page 50).9 Substantially in- Drexel University College of Medicine Philadelphia, PA creased serum PRL levels may be seen with: † • , which usually present as inciden- Elizabeth B. Weller, MD Professor of Psychiatry and Pediatrics tal findings on a brain CT or MRI or with symptoms of University of Pennsylvania tumor mass Children’s Hospital of Philadelphia • a craniopharyngioma or other tumor that com- Philadelphia, PA Current Psychiatry presses the pituitary stalk or and in- †Deceased November 29, 2009 Vol. 10, No. 5 47 Box 1 What controls production of prolactin?

rolactin (PRL) is a lactogenic polypeptide delivered via the hypothalamic- Phormone with a structure that resembles pituitary portal circulation. Its production is human growth and human placental stimulated and inhibited by several molecular lactogen. A single gene on chromosome 6 factors. Under most conditions the predominant encodes PRL, which is composed of 199 signal for PRL secretion from the pituitary Prolactin amino acids.1 is under inhibitory control. This is primarily elevation PRL is produced primarily by lactotroph mediated by the neurotransmitter dopamine, cells in the anterior , but also is which is a tonic inhibitor of PRL expression and produced and is active in breast tissue and thus prevents its release. Other inhibitors of mammary glands, and decidua, bone PRL are triiodothyronine (T3) and somatostatin.2 marrow cells, lymphocytes (T cells and B Molecular stimulators of PRL production cells), and other tissues. It has >300 biologic include thyrotropin-releasing factor, vasoactive activities.1 intestinal peptide, peptide histidine isoleucine, PRL acts primarily through receptors that -releasing hormone, and . belong to the large class-1 cytokine receptor These 5 molecular stimulators all enhance the superfamily. PRL receptors have multiple growth of PRL-producing cells.1 The balance Clinical Point isoforms in many different tissues. between these stimulatory and inhibitory signals Like most hormones, determines the amount of PRL released from the Atypical PRL is under dual regulation by hypothalamic anterior pituitary. antipsychotics cause less elevation in prolactin levels terrupts the hypothalamic-dopa­minergic tion and is associated with increased PRL than conventional inhibition of PRL release.10 release.12 antipsychotics Primary failure (hypothyroid- ism) can produce a compensatory increase Atypical antipsychotics cause less eleva- in the discharge of central hypothalamic tion in PRL levels than conventional anti- thyrotropin-releasing hormone, resulting psychotics. This may be because of their: in increased stimulation of PRL secretion.10 • highly selective mesolimbic and meso­ Medications can increase serum PRL cortical dopamine receptor antagonism, (Table 2, page 54)9 and cause clinical symp- which spares dopamine blockade within toms similar to those of physiologically in- the tuberoinfundibular tract duced hyperprolactinemia. • relatively lower D2 receptor affinity.11 and its active metabolite Conventional antipsychotics. The anti­ paliperidone (9-hydroxyrisperidone) have psychotic potency of phenothiazines, a high affinity for D2 receptors and thus thioxanthenes, butyrophenones, and have potent D2 antagonistic effects.12,13 At dibenzoxazepines generally parallels dosages of 8 mg/d to 11.8 mg/d, risperi- their potency in increasing PRL levels.9 done and paliperidone are associated with Although a dose-response relationship the greatest increase in PRL levels among between PRL concentrations and conven- atypical antipsychotics.14 tional antipsychotics is likely, immediate The rate of risperidone metabolism de- and pronounced increases in PRL can oc- pends on the patient’s cytochrome P (CYP) cur even with low doses. 2D6 enzyme genotype. “Extensive” ONLINE ONLY Prospective studies have shown that 3 CYP2D6 metabolizers convert risperi- to 9 weeks of treatment with an antipsy- done rapidly into 9-hydroxyrisperidone, Discuss this article at chotic such as chlorpromazine increased whereas “poor” CYP2D6 metabolizers www.facebook.com/ mean baseline PRL levels up to 10-fold, convert it much more slowly. Six percent CurrentPsychiatry even at therapeutic doses.11 Conventional to 8% of white individuals and a very antipsychotics can cause marked increases low percentage of Asians have little or no in PRL, probably by blocking dopamine CYP2D6 activity and are “poor metabo- receptors in the tuberoinfundibular tract.12 lizers.” CYP2D6 also is inhibited by vari- The blockage of D2 receptors removes the ous substrates and nonsubstrates, notably Current Psychiatry 48 May 2011 main inhibitory influence on PRL secre- quinidine. Although extensive metabo- Box 2 Prolactin: A versatile hormone with many roles

rolactin (PRL) is best known for its gonadotropin-releasing hormone and as a Pregulatory role in reproductive processes. result suppresses during .3 It inhibits secretion of the pituitary hormones PRL also maintains luteal vascularization in ( [LH] and follicle-stimulating early .1 hormone [FSH]), which are responsible for PRL also has a role in bone development gonadal function. PRL also influences normal and bone mass maintenance. It has a direct breast development, lactation following inhibitory effect on osteoblast function, , and corpus luteum development. possibly through an effect on estrogen.5 It plays a critical role in inducing and Although the mechanism is unclear, sustained maintaining mammary epithelial and plasma PRL elevation decreases bone differentiation.1 formation, leading to reduced bone mineral A recently observed correlation between density and increased risk of hip fracture.6 elevated plasma PRL and PRL is a stimulatory modulator of immune development suggests a mitogenic action in function and may be a “stress hormone.” It breast tissue. A prospective, case-control study is widely produced by lymphocytes. PRL and of 851 women from the Nurses’ Health Study its receptors are expressed on diverse bone cohort found a “modestly” increased relative risk marrow-derived human cell types, including Clinical Point of postmenopausal breast cancer associated B cells, T cells, monocytes, natural killer cells, with PRL plasma concentrations (1.34; 95% and cluster of differentiation 34 (CD34) human Prolactin elevation confidence interval, 1.02 to 1.76).3 stem cells.7 The widespread expression of is greater in children PRL also acts as a physiologic sensor during PRL receptors on hematopoietic and immune lactation. It regulates ductal side branching and cells implies a role in immunohematopoietic than in directly controls lobuloalveolar development and system development. lactogenesis (synthesis of ) in breast tissue. Other functions of PRL include regulation part because of PRL is stimulated by suckling; it responds to of pancreatic islets growth and function increased density demands for milk production by partitioning during the perinatal period; osmoregulation nutrients such as calcium away from adipose in mammary glands, amniotic membranes, of D2 receptors in tissue and into the mammary glands.1,4 and the intestinal epithelial membrane; and developing striatum In reproduction, PRL can have a luteotropic maintenance of positive calcium deposition.1 or luteolytic action, depending on the stage of As a potent platelet aggregation co-activator, the reproductive cycle. It negatively modulates prolactin also may be a risk factor for both LH and FSH secretion by suppressing arterial and venous thrombosis.8

lizers have lower risperidone and higher psychotics have been treated subsequently 9-hydroxyrisperidone concentrations than with clozapine without hyperprolactinemia poor metabolizers, the pharmacokinetics recurrence.16 Iloperidone has been associ- of the active moiety after single and multi- ated with decreased PRL levels.17 ple doses are similar in extensive and poor metabolizers.15 Antidepressants that work by blocking Clozapine, , , catecholamine reuptake also cause hyperp- ziprasidone, and aripiprazole are associat- rolactinemia. This increase may be related ed with a much lower risk of PRL elevation to the antidopaminergic, stimulatory effects than risperidone. In an 8-week open-label of estrogen. Numerous cases of galactor- trial, aripiprazole (mean dose 9.4 ± 4.2 rhea and amenorrhea have been reported mg/d), did not increase serum PRL in 15 with the use of selective serotonin reuptake children and adolescents.2 inhibitors (SSRIs).16 Galactorrhea has been Ziprasidone may cause only transient reported in women who took venlafaxine.12 PRL elevation.16 PRL abnormalities may be Less is known about the effects of nefazodo- least likely with clozapine and quetiapine, ne or bupropion on serum PRL. Mirtazapine possibly because of their relatively lower can decrease serum PRL in men, probably D2 receptor affinity. Amenorrhea, galac- through indirect 5-HT1 agonist and 5-HT2 torrhea, or inhibition of have and 5-HT3 antagonist activity.16 not been reported with the use of these 2 PRL elevation is greater in children antipsychotics.16 Patients who developed and adolescents than adults because of Current Psychiatry hyperprolactinemia on conventional anti- increased density of D2 receptors in the Vol. 10, No. 5 49 Table 1 in mice.18 To determine if there was a similar association in humans, Szarfman Causes of hyperprolactinemia et al18 retrospectively evaluated data on Iatrogenic causes 7 antipsychotics—aripiprazole, clozapine, Conventional antipsychotics (phenothiazines, olanzapine, quetiapine, risperidone, zipra- thioxanthenes, butyrophenones, sidone, and haloperidol—and found 77 pi- dibenzoxazepines) tuitary tumors associated with use of these Prolactin Atypical antipsychotics (risperidone, medications. Risperidone was associated elevation olanzapine, ziprasidone, clozapine, quetiapine, with 54 of the pituitary tumors—including aripiprazole, paliperidone) 3 in adolescents age 14 to 16. No pituitary SSRIs (fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram) tumors were reported with aripiprazole. Approximately one-half of the pituitary Antiretroviral agents (ritonavir, indinavir, zidovudine) tumors were benign. Symptoms included Gastrointestinal agents (omeprazole, ranitidine, visual field defects, headaches, pituitary , famotidine) hemorrhage, convulsions, and coma. Other medications (oral contraceptives, Other adverse effects reported in the Clinical Point verapamil, , reserpine, triptorelin, study were hyperprolactinemia, galactor- bendroflumethiazide) rhea, amenorrhea, and . The Hyperprolactinemia Other causes may lead to incidence of adverse effects with risperi- Tumors (, craniopharyngioma, done was >10-fold higher than with halo- other cerebral tumor) delayed , peridol or olanzapine and >25-fold higher Ectopic prolactin synthesis (bronchial amenorrhea, short carcinoma, acromegaly, empty sella syndrome, than with clozapine, ziprasidone, quetiap- stature, infertility, polycystic ovarian syndrome) ine, and aripiprazole. and osteopenia or Chronic renal failure Hyperprolactinemia secondary to mac- roadenoma or microadenoma in children osteoporosis Primary thyroid failure Physiological causes (pregnancy, lactation, and adolescents is rare and difficult to stress, sleep, , head injury, diagnose because typically it is suspected surgery) only when symptoms of tumor expansion

SSRIs: selective serotonin reuptake inhibitors occur. The usual initial symptoms of mi- Source: Reference 9 croadenomas are menstrual disturbances and galactorrhea in girls and galactorrhea and gynecomastia in boys.19 developing striatum and differential D2 receptor sensitivity in the tuberoinfun- Decreased bone mass. Long-term hy- dibular tract.16 Unfortunately, few studies perprolactinemia may lead to delayed pu- have examined the consequences of elevat- berty, primary amenorrhea, short stature, ed PRL in children and adolescents. infertility, and osteopenia and/or osteopo- rosis due to decreased bone mass density (BMD).16 The risk of osteoporosis and/or Clinical features osteopenia is directly related to the dura- Adenomas. Primary hyperprolactinemia tion of hyperprolactinemia. A serum PRL related to excessive secretion from the pi- level twice the upper limit of normal can tuitary and other tissues causes multiple result in osteopenia. clinical effects, including: • amenorrhea, oligomenorrhea, anovu- Breast cancer risk may be increased in hy- latory cycles, galactorrhea, , perprolactinemia because of the effects of , infertility, hirsutism, PRL on breast tissue and and loss of libido in development. A study of premenopausal • impotence, loss of libido, decrease in (n = 235) and postmenopausal women (n = seminal fluid volume, galactorrhea, and 851) reported a positive correlation between gynecomastia in males.12 elevated PRL levels and breast cancer risk.3 Preclinical studies of risperidone suggest- “Crosstalk” between PRL and Current Psychiatry 50 May 2011 ed an association with pituitary adenomas in activating AP-1 activity may promote continued on page 54 continued from page 50

Table 2 creased PRL levels and resultant effects. For example, the BMD of adolescent girls Relative risk of hyperprolactinemia with 6 months of hypothalamic-pituitary- with common psychotropics gonadal (HPG) axis dysfunction caused Effect on prolactin by hyperprolactinemia was reduced by 2 Medication serum levels standard deviations (SDs) below the popu- Antipsychotics lation mean.16 A BMD 1 SD below the mean Prolactin Phenothiazines ++ age-population value may double the risk 16 elevation Butyrophenones ++ for fractures. Unfortunately, there are no Thioxanthenes ++ studies that measure estrogen levels or BMDs of children taking psychotropics16 Risperidone ++ or that assess PRL in pubertal girls taking Quetiapine + atypical antipsychotics or SSRIs. Olanzapine + Clozapine 0 Ziprasidone 0 Evaluation of hyperprolactinemia Clinical Point Aripiprazole 0 Blood samples to measure PRL levels The degree of change SSRIs must be collected under standardized Paroxetine +/- in serum prolactin conditions. A morning fasting serum PRL Citalopram +/- level should be obtained between 8 am levels over time may Fluvoxamine +/- and 10 am (3 hours after waking up). It is be more important Fluoxetine CR best to avoid emotional stress or strenu- than absolute 0: no hyperprolactinemia effect; +/-: increased but not ous exercise for at least 30 minutes before to abnormal levels; +: increased to abnormal in small the blood draw because these conditions prolactin level percentage of patients; ++: increased to abnormal in >50% of patients; CR: isolated case reports of can raise PRL. Avoid stimulation hyperprolactinemia but generally no increase to abnormal for 24 hours before testing because this SSRIs: selective serotonin reuptake inhibitors Source: Adapted from reference 9 also can raise PRL levels. A woman hav- ing abnormal should not do anything to cause more discharge carcinogenesis. Furthermore, tamoxifen, a before the test. Serum PRL levels should common treatment for breast cancer, lowers be monitored every 6 months in pubertal PRL concentrations.3 girls taking psychotropics until they ex- Not all patients with hyperprolac- perience sexual maturity or regular men- tinemia develop problems. Whether strual cycles so that abnormalities can be hyperprolactinemia secondary to antipsy- identified early and irreversible BMD loss chotic treatment adversely affects bone is minimized.16 density or sexual maturation is unknown. Absolute PRL level is not useful in guid- Furthermore, sexual side effects—such as ing treatment because it is not consistently a decrease or loss of libido, erectile dys- correlated with adverse effects. However, function, impotence, and ejaculatory or or- the degree of change of serum PRL levels gasmic difficulties—do not show a strong over time or the change of PRL levels from correlation with PRL levels.11 baseline may be important in diagnos- Effects of hyperprolactinemia may be ing asymptomatic hyperprolactinemia.16 more pronounced in adolescents because Suspect pathologic hyperprolactinemia in PRL synthesis and release are stimulated patients (except newborns and pregnant by estrogen. In adolescent females elevat- women) with plasma PRL levels consistent- ed estrogen levels can be related to: ly >15 to 25 ng/mL.12 This finding occurs in • increased estrogen levels in menstru- <1% of the population, but the rate is higher ating females among individuals with specific symp- • increased estrogen levels in females toms attributable to hyperprolactinemia. taking oral contraceptives.16 For example, 9% of women with amenor- Therefore, adolescent females tak- rhea, 25% of women with galactorrhea, and Current Psychiatry 54 May 2011 ing antipsychotics are at high risk for in- 70% of women with both amenorrhea and Table 3 Presenting symptoms of hyperprolactinemia

Adult females males Prepubertal children (male and female) Amenorrhea Decreased in seminal Delayed puberty Anovulatory cycle fluid volume Galactorrhea Breast enlargement Galactorrhea Gynecomastia Breast pain Gynecomastia Osteopenia or osteoporosis Galactorrhea Impotence Primary amenorrhea (females only) Hirsutism Loss of libido Short stature Infertility Loss of libido Oligomenorrhea Source: Adapted from reference 12

galactorrhea have hyperprolactinemia. The nonfunctioning adenoma.12 Antipsychotics Clinical Point prevalence is approximately 5% among usually produce moderate PRL elevation In pubertal girls taking 10 men with impotenceor infertility. (up to 6 times the upper limit of the ref- agents that modulate If hyperprolactinemia is detected, the erence range of 100 ng/mL).12 In 1 study, degree of PRL elevation can help deter- the median time to onset of galactorrhea prolactin, consider mine etiology. In the absence of pregnancy was 20 days after initiating antipsychotics monitoring prolactin and breast-feeding, a serum PRL level of in female patients.12 Hyperprolactinemia- levels every 6 months >600 ng/mL is highly suggestive of a mac- induced HPG axis dysfunction causes until patients achieve roprolactinoma.12 PRL concentrations >250 delayed pubertal development or loss of ng/mL suggest a microprolactinoma or a bone mineral deposit.16 Measuring BMD in sexual maturity

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Individual and institutional subscriptions available. Subscription includes both print and online access. Call 800-480-4851 or e-mail [email protected] Individual subscription rates are $150 U.S. and $175* international. *price includes airmail delivery will help to determine if the PRL elevation Related Resource is caused by one of these factors. • Ali J, Khemka M. Hyperprolactinemia: Monitoring chil- To treat hyperprolactinemia, address dren on long-term risperidone. Current Psychiatry. 2008;7(11):64-72. the underlying medical cause(s). If pa- Drug Brand Names tients using antipsychotics have signs and Amantadine • Symmetrel Nefazodone • Serzone symptoms of hyperprolactinemia, con- Aripiprazole • Abilify Olanzapine • Zyprexa sider discontinuing the drug or reducing Bendroflumethiazide Omeprazole • Prilosec the dosage.11 If dose change fails to reduce Prolactin • Naturetin Paliperidone • Invega elevation Bromocriptine • Parlodel Paroxetine • Paxil hyperprolactinemia, consider a switch to Bupropion • Wellbutrin Quetiapine • Seroquel a low-potency D2 agent or aripiprazole. • Dostinex Quinidine • Quinidex 20 Chlorpromazine • Thorazine Ranitidine • Zantac Shim et al studied the effects of adjunc- Cimetidine • Tagamet Reserpine • Serpasil tive treatment with aripiprazole on hy- Citalopram • Celexa Risperidone • Risperdal Clozapine • Clozaril Ritonavir • Norvir perprolactinemia and psychopathology in Famotidine • Pepcid Sertraline • Zoloft schizophrenia patients maintained on halo- Fluoxetine • Prozac Tamoxifen • Nolvadex Fluvoxamine • Luvox Triptorelin • Trelstar peridol. In this study, aripiprazole reversed Haloperidol • Haldol Venlafaxine • Effexor hyperprolactinemia in both but plas- Clinical Point Iloperidone • Fanapt Verapamil • Calan, Isoptin ma levels of haloperidol were not signifi- Indinavir • Crixivan Zidovudine • Retrovir If reducing the Methyldopa • Aldomet Ziprasidone • Geodon cantly altered. The authors hypothesized Mirtazapine • Remeron dosage that decreased PRL levels may have been Disclosure the result of pharmacodynamic interaction fails to reduce The authors report no financial relationship with any com- at dopamine receptors rather than pharma- pany whose products are mentioned in this article or with hyperprolactinemia, manufacturers of competing products. cokinetic interaction between aripiprazole and haloperidol. Additional studies are consider switching Acknowledgment needed to confirm these findings. to a low-potency D2 The authors wish to thank Yunyoung C. Chang, BS, for her assis- tance with this article. If a medication switch is contraindi- agent or aripiprazole cated, pharmacologic treatment for hy- perprolactinemia may be required.11 Bromocriptine, cabergoline, and amanta- dine have been used to treat hyperprolac- children and adolescents with hyperpro- tinemia.11 Bromocriptine lowers PRL levels lactinemia is important during this critical and restores normal gonadal function for time of skeletal development.16 men and women with hyperprolactinemia regardless of etiology, but may worsen psy- chiatric symptoms and can cause nausea, Managing hyperprolactinemia headaches, dizziness, and orthostatic hypo- Before starting any antipsychotic, inform pa- tension.11 In a pilot study, amantadine, 300 tients and families of possible side effects, in- mg/d, used to treat neuroleptic-induced cluding hyperprolactinemia. Educate them extrapyramidal effects also decreased PRL about recognizing the signs and symptoms levels and reduced galactorrhea.11 of hyperprolactinemia (Table 3, page 55).12 Osteoporosis can be minimized by ex- Although PRL blood levels typically are ercising, taking adequate calcium and vi- not routinely measured in pubertal girls tamin D, and avoiding caffeinated drinks.9 who take PRL-modulating agents, con- Simmons et al21 found bisphosphonate treat- sider monitoring serum PRL levels every 6 ment in children and adolescents improved months until patients achieve sexual matu- bone density and fragility within 2 to 4 years. rity and regularity.16 Unfortunately, information about optimal If laboratory testing detects elevated duration and long-term effects of bisphos- PRL levels in a child or adolescent, deter- phonate therapy is limited.22 mine if the patient had sexual intercourse, Surgical treatment may be necessary to nipple stimulation, stress (including ve- remove a pituitary tumor that causes hy- nipuncture), sleep disturbances, seizures, perprolactinemia. For some patients, refer- head injury, or surgery before the blood ral to pediatric endocrinologist for further Current Psychiatry 56 May 2011 sample was obtained. This information treatment may be needed. References 12. Haddad PM, Wieck A. Antipsychotic-induced hyper- 1. Freeman ME, Kanyicska B, Lerant A, et al. Prolactin: prolactinaemia: mechanisms, clinical features and structure, function, and regulation of secretion. Physiol Rev. management. Drugs. 2004;64(20):2291-2314. 2000;80(4):1523-1631. 13. Nussbaum A, Stroup T. Paliperidone for treatment of 2. Biederman J, Mick E, Spencer T, et al. An open-label trial of schizophrenia. Schizophr Bull. 2008;34(3):419-422. aripiprazole monotherapy in children and adolescents with 14. Findling R, Kusumakar V, Daneman D, et al. Prolactin bipolar disorder. CNS Spectr. 2007;12(9):683-689. levels during long-term risperidone treatment in 3. Tworoger SS, Eliassen AH, Rosner B, et al. Plasma prolactin children and adolescents. J Clin Psychiatry. 2003;64(11): concentrations and risk of postmenopausal breast cancer. 1362-1369. Cancer Res. 2004;64(18):6814-6819. 15. Risperdal [package insert]. Titusville, NJ: Ortho-McNeil- 4. Anantamongkol U, Takemura H, Suthiphongchai T, et al. Janssen Pharmaceuticals, Inc; 2010. Regulation of Ca2+ mobilization by prolactin in mammary 16. Becker A, Epperson CN. Female puberty: clinical implications gland cells: possible role of secretory pathway Ca2+- ATPase for the use for prolactin-modulating psychotropics. Child type 2. Biochem Biophy Res Commun. 2007;352(2):537-542. Adolesc Psychiatr N Am. 2006;15(1):207-220. 5. Coss D, Yang L, Kuo CB, et al. Effects of prolactin on 17. Weiden PJ, Cutler AJ, Polymeropoulos MH, et al. Safety osteoblast alkaline phosphatase and bone formation profile of iloperidone: a pooled analysis of 6-week acute- in the developing rat. Am J Physiol Endocrinol Metab. phase pivotal trials. J Clin Psychopharmacol. 2008;28 2000;279(6):1216-1225. (2 suppl 1):S12-S19. 6. Meaney AM, O’Keane V. Bone mineral density changes over 18. Szarfman A, Tonning J, Levine J, et al. Atypical a year in young females with schizophrenia: relationship antipsychotics and pituitary tumors: a pharmacovigilance to medication and endocrine variables. Schizophr Res. study. Pharmacotherapy. 2006;26(6):748-758. 2007;93(1-3):136-143. 19. Colao A, Loche S, Cappa M, et al. Prolactinoma in 7. Richards SM, Murphy WJ. Use of human prolactin as a children and adolescents. Clinical presentation and therapeutic protein to potentiate immunohematopoietic long-term follow-up. J Clin Endocrinol Metab. 1998;83(8): function. J Neuroimmunol. 2000;109(1):56-62. 2777-2780. Clinical Point 8. Wallaschofski H, Donné M, Eigenthaler M, et al. PRL as 20. Shim JC, Shin JG, Kelly DL, et al. Adjunctive treatment with a novel potent cofactor for platelet aggregation. J Clin a dopamine partial agonist, aripiprazole, for antipsychotic- Bromocriptine, Endocrinol Metab. 2001;86(12):5912-5919. induced hyperprolactinemia: a placebo-controlled trial. Am 9. Molitch M. Medication-induced hyperprolactinemia. Mayo J Psychiatry. 2007;164:1404-1410. cabergoline, and Clin Proc. 2005;80(8):1050-1057. 21. Simmons J, Zeitler P, Steelman J. Advances in the 10. Serri O, Chik CL, Ur E, et al. Diagnosis and management of diagnosis and treatment of osteoporosis. Adv Pediatr. amantadine have hyperprolactinemia. CMAJ. 2003;169(6):575-581. 2007;54:85-114. 11. Compton M, Miller A. Antipsychotic-induced hyper- 22. Ward L, Tricco AC, Phuong P, et al. Bisphosphonate therapy been used to treat prolactinemia and sexual dysfunction. Psychopharmacol for children and adolescents with secondary osteoporosis. Bull. 2002;36(1):143-164. Cochrane Database Syst Rev. 2007;(4):CD005324. hyperprolactinemia

Bottom Line , pituitary disorder, antipsychotics, and other conditions and medications can cause hyperprolactinemia, which can substantially effect growth and development in children and adolescents. Treatment should focus on addressing Current Psychiatry underlying medical causes and/or medication reduction or discontinuation. Vol. 10, No. 5 57