Antipsychotic induced hyperprolactinaemia mechanisms, clinical features and management

Drugs 2004; 64 (20): 2291-2314REVIEW ARTICLE 0012-6667/04/0020-2291/$34.00/0

2004 Adis Data Information BV. All rights reserved.

Antipsychotic-Induced HyperprolactinaemiaMechanisms, Clinical Features and Management

Peter M. Haddad1,2 and Angelika Wieck2,3

1 Bolton, Salford & Trafford Mental Health NHS Trust, Salford, UK2 Department of Psychiatry, University of Manchester, Manchester, UK3 Manchester Mental Health and Social Care Trust, Manchester, UK

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22921. Prolactin Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2293

1.1 Normal Serum Prolactin Levels and Physiological Functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22931.2 Inhibitory Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22931.3 Stimulatory Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22941.4 Hyperprolactinaemia and the Hypothalamic-Pituitary-Gonadal Axis . . . . . . . . . . . . . . . . . . . . . 2294

2. Effects of Antipsychotic and Other Psychotropic Drugs on Prolactin Secretion . . . . . . . . . . . . . . . . . 22942.1 Research in Unmedicated Patients with Psychiatric Illness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22942.2 Conventional Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22952.3 Atypical Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22962.4 Reasons for Differential Effect of Antipsychotics on Prolactin Secretion . . . . . . . . . . . . . . . . . . . 22972.5 Other Psychotropic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2298

3. High-Risk Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22983.1 Women . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22983.2 The Postnatal Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22983.3 Children and Adolescents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22993.4 Other High-Risk Groups . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2299

4. Symptoms of Hyperprolactinaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22994.1 Gynaecomastia and Galactorrhoea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23004.2 Sexual Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23014.3 Menstrual Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23024.4 Infertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23034.5 Disease-Related Dysfunction of the Hypothalamic-Pituitary-Gonadal Axis . . . . . . . . . . . . . . . . 2303

5. Effects on Bone Mineral Density (BMD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23045.1 Measurement of BMD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23045.2 Effect of Hypogonadism Unrelated to Antipsychotics on BMD . . . . . . . . . . . . . . . . . . . . . . . . . . . 23045.3 Non-Endocrine Risk Factors for Osteoporosis in Psychiatric Patients . . . . . . . . . . . . . . . . . . . . . . . 23055.4 Studies of BMD in Psychiatric Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2305

6. Possible Relationship with Breast Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23067. Investigations and Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23078. Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2308

8.1 Is Intervention Warranted? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23088.2 Treatment Options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2309

9. Conclusions and Future Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2310

2292 Haddad & Wieck

Hyperprolactinaemia is an important but neglected adverse effect of anti-Abstractpsychotic medication. It occurs frequently with conventional antipsychotics andsome atypical antipsychotics (risperidone and amisulpride) but is rare with otheratypical antipsychotics (aripiprazole, clozapine, olanzapine, quetiapine, ziprasi-done). For this reason the terms ‘prolactin-sparing’ and ‘prolactin-raising’ aremore useful than ‘atypical’ and ‘conventional’ when considering the effect ofantipsychotic drugs on serum prolactin.

During antipsychotic treatment prolactin levels can rise 10-fold or more abovepretreatment values. In a recent study approximately 60% of women and 40% ofmen treated with a prolactin-raising antipsychotic had a prolactin level above theupper limit of the normal range. The distinction between asymptomatic andsymptomatic hyperprolactinaemia is important but is often not made in theliterature. Some symptoms of hyperprolactinaemia result from a direct effect ofprolactin on target tissues but others result from hypogonadism caused by prolac-tin disrupting the normal functioning of the hypothalamic-pituitary-gonadal axis.

Symptoms of hyperprolactinaemia include gynaecomastia, galactorrhoea, sex-ual dysfunction, infertility, oligomenorrhoea and amenorrhoea. These symptomsare little researched in psychiatric patients. Existing data suggest that they arecommon but that clinicians underestimate their prevalence. For example, wellconducted studies of women treated with conventional antipsychotics have report-ed prevalence rates of approximately 45% for oligomenorrhoea/amenorrhoea and19% for galactorrhoea. An illness-related under-function of the hypothalamic-pituitary-gonadal axis in female patients with schizophrenia may also contributeto menstrual irregularities. Long-term consequences of antipsychotic-relatedhypogonadism require further research but are likely and include premature boneloss in men and women. There are conflicting data on whether hyperprolactin-aemia is associated with an increased risk of breast cancer in women.

In patients prescribed antipsychotics who have biochemically confirmedhyperprolactinaemia it is important to exclude other causes of prolactin elevation,in particular tumours in the hypothalamic-pituitary area. If a patient has beenamenorrhoeic for 1 year or more, investigations should include bone mineraldensity measurements. Management should be tailored to the individual patient.Options include reducing the dose of the antipsychotic, switching to a prolactin-sparing agent, prescribing a dopamine receptor agonist and prescribing estrogenreplacement in hypoestrogenic female patients. The efficacy and risks of the lasttwo treatment options have not been systematically examined.

Antipsychotic-induced hyperprolactinaemia should become a focus of interestin the drug treatment of psychiatric patients, particularly given the recent intro-duction of prolactin-sparing antipsychotics. Appropriate investigations and effec-tive management should reduce the burden of adverse effects and prevent long-term consequences.

It has been recognised for more than 25 years that hyperprolactinaemia has been relatively neglected.antipsychotic drugs can elevate serum prolactin and A recent survey indicated that both psychiatrists andthat this can cause various clinical manifestations.[1] psychiatric nurses tended to underestimate the prev-Despite this the syndrome of antipsychotic-induced alence of key symptoms associated with hyperpro-

2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (20)

Antipsychotic-Induced Hyperprolactinaemia 2293

lactinaemia.[2] Certainly the extrapyramidal effects Despite significant variation in serum prolactinof antipsychotics have attracted far more research values, both within- and between-individuals, thereand clinical interest. For example, our search of the is a reasonable consensus regarding the upper limitMedline database (1966–2004) in July 2004, using of the normal range. Bevan[6] cites this as beingthe terms ‘antipsychotics and extrapyramidal symp- 500 mU/L in both men and women, that is approxi-toms’ revealed 1717 journal articles, whereas a mately 15 µg/L (15 ng/mL). However, some author-search on ‘antipsychotics and hyperprolactinaemia’ ities suggest an upper limit of 25 µg/L (approxi-revealed only 375 articles. mately 800 mU/L).[7,8] Serum prolactin levels are

sometimes given as nanomoles per litre. The con-In this review we discuss the physiology of pro-version factor between the units differs somewhatlactin secretion, the effect of conventional and atypi-depending on the radioimmunoassays used but 1 µg/cal antipsychotic drugs on serum prolactin levelsL is approximately equivalent to 30 mU/L orand the clinical manifestations of hyperprolactin-0.043 nmol/L.[6]aemia in men and women. Since antipsychotic treat-

ment is often initiated when patients are in their late In women serum prolactin levels increase duringteens or 20s and continued for years or decades, we pregnancy to reach levels 10–20 times the non-also consider the possible consequences of pro- pregnant value. Although there is marked individuallonged endocrine dysfunction, particularly with re- variation, prolactin levels can reach 200 µg/L (ap-spect to bone mineral density (BMD). The investi- proximately 6500 mU/L) at term and 300 µg/L (ap-gations and differential diagnosis of the patient proximately 9000 mU/L) during nursing.[9] In thetreated with an antipsychotic drug who has bio- absence of breast-feeding, serum prolactin levelschemically confirmed hyperprolactinaemia are dis- fall to normal within approximately 3 weeks aftercussed, as is the subsequent management. child birth. Levels normalise after several months in

breast-feeding women.1. Prolactin Physiology The main physiological function of prolactin is to

cause breast enlargement during pregnancy andmilk production during lactation. The reductions in1.1 Normal Serum Prolactin Levels andlibido and fertility that are associated with nursingPhysiological Functionsmay have evolutionary advantages. Prolactin is

Prolactin is a 199-amino acid polypeptide hor- known to have an important function in promotingmone that is secreted by the lactotroph cells in the maternal behaviour in animals but its role in humansanterior pituitary. It is released in a pulsatile manner is not known in this respect.with 13–14 peaks per day and an interpulse intervalof about 95 minutes. The mean pulse amplitude 1.2 Inhibitory Factorsrepresents a 58% increase above the preceding na-dir.[3] Prolactin levels show a marked circadian vari- The secretion of prolactin is under the complexation. The maximum level is reached about 4 hours control of peptide and steroid hormones and neuro-after the onset of sleep and is approximately 160% transmitters, which act as both inhibitory and stimu-of the 24-hour mean. The minimum level is reached latory factors.[10] Dopamine is the predominant pro-about 6 hours after waking and is approximately lactin-inhibiting factor in animals and humans. It is40% of the 24-hour mean.[4] As a result, prolactin produced by the tuberoinfundibular neurons in thelevels can vary up to 4-fold depending on the time of hypothalamus, released from their nerve endings inday or night. Transient and mild increases of prolac- the median eminence and transported by the portaltin levels occur in response to meals, stress and hypophyseal circulation to the pituitary, where itsexual activity.[5] In women prolactin levels are binds to the dopamine D2 receptors on the mem-higher during mid cycle and the second half of the brane of lactotroph cells.[11] D2 receptor stimulationmenstrual cycle. has effects on prolactin gene transcription, synthesis


2294 Haddad & Wieck

and release and these are mediated in a complex tradiol on LH secretion. The end result is that highfashion, involving several signal transduction sys- circulating prolactin levels can cause reduced gona-tems.[5,10] Gonadotropin-associated protein and ace- dal hormone levels (i.e. reduced estrogen levels intylcholine have been identified as prolactin-inhibit- women and reduced testosterone levels in men) anding factors in animals but their physiological signifi- this can present with a variety of symptoms. Therecance in humans is uncertain.[5,10] appears to be marked individual variation in the

prolactin level at which gonadal under-function oc-1.3 Stimulatory Factors curs. According to Marken et al.,[7] amenorrhoea

usually develops at a serum prolactin level aboveAnimal and human studies demonstrate that sero-

60–100 µg/L (approximately 2000–3000 mU/L), al-tonin stimulates prolactin secretion and is involved

though in our experience amenorrhoea can bein the mediation of nocturnal surges and suckling-

caused by much lower prolactin values.induced rises.[12] The serotonergic neurons involvedproject from the dorsal raphe nucleus to the medial 2. Effects of Antipsychotic and Otherbasal hypothalamus and exert their effects via sero- Psychotropic Drugs ontonin 5-HT1A and 5-HT2 receptor mechanisms. Prolactin Secretion

Estrogens have an important regulatory functionVirtually all antipsychotic drugs have the capa-in prolactin secretion. They bind to specific intra-

city to block D2 receptors, and indeed D2 receptorcellular receptors in lactotrophs and can enhanceblockade in the mesolimbic and mesocortical areasprolactin gene transcription and synthesis as well asappears integral to antipsychotic efficacy. However,DNA synthesis and mitotic activity.[5] In animalin other brain areas D2 receptor blockade can causestudies estrogens have also been shown to counter-adverse effects. Parkinsonism results from D2 recep-act the effect of dopamine by inhibiting dopaminetor blockade in the striatum, while blockade of D2synthesis in the tuberoinfundibular neurons in somereceptors on lactotroph cells causes hyperprolactin-species[13] and reducing D2 receptor levels on lacto-aemia, as it removes the main inhibitory influencetrophs.[14]

on prolactin secretion. When considering anti-Several peptide neurotransmitters, includingpsychotic-induced hyperprolactinaemia it is impor-thyrotropin-releasing hormone and cholecystokinin,tant to differentiate between asymptomatic andhave prolactin-releasing properties in animals.[10]

symptomatic hyperprolactinaemia. Many researchGABA has both stimulatory and inhibitory effectspapers reporting clinical trials of antipsychotics areon prolactin secretion.[15] The physiological role oflimited to reporting the prevalence of hyperpro-these substances in humans is uncertain.lactinaemia (i.e. the proportion of patients with a

1.4 Hyperprolactinaemia and the serum prolactin above the upper limit of normal)Hypothalamic-Pituitary-Gonadal Axis without determining whether this causes symptoms.

High prolactin levels inhibit the hypothalamic- 2.1 Research in Unmedicated Patients withpituitary-gonadal axis at several levels. Under nor- Psychiatric Illnessmal physiological conditions, in both men andwomen, gonadotropin-releasing hormone (GnRH) is Several studies have compared mean serum pro-secreted in a pulsatile manner from the hypothala- lactin levels in unmedicated patients with schizo-mus and stimulates the release of luteinising hor- phrenia and healthy controls.[16-20] A consistent find-mone (LH) and follicle-stimulating hormone (FSH) ing is that prolactin levels are not elevated in un-from the anterior pituitary. Prolactin inhibits the medicated schizophrenic patients. Indeed, there isrelease of GnRH by the hypothalamus and also some evidence[16] that, compared with healthyinhibits its action at the pituitary. In women prolac- women, female drug-free schizophrenic patientstin also blocks the positive feedback effect of es- have a lower daily mean prolactin level and lower



amplitude of the circadian variation of serum prolac- doses of antipsychotics increases mean baseline pro-tin, findings that are consistent with schizophrenia lactin levels up to 10-fold.[25-29]

being associated with increased dopaminergic ac- Low daily dosage regimens (e.g. chlorpromazinetivity. A study of men with endogenous depression 200mg) can cause significant prolactin elevations[24]

and age-matched healthy men showed no difference and levels have been reported to increase in a dose-in 24-hour mean prolactin levels.[21]

dependent manner up to about chlorpromazineUnmedicated patients with schizophrenia show a 600mg equivalents.[30,31] A significant correlation

phase advance of circadian serum prolactin levels between the dose of conventional antipsychotic drugcompared with healthy controls, with the peak pro- and the serum prolactin level was seen in a recentlactin level being reached 1.5 hours earlier.[16,17] UK study of 67 outpatients with schizophrenia.[32] InThis phase shift is not corrected by antipsychotic one study from the 1970s there was a tendency fortreatment. A prolactin phase advance of a similar thioridazine to produce higher prolactin levels thanmagnitude has been demonstrated in patients with therapeutically equivalent doses of trifluoperazineunipolar depression.[21] The significance of these or chlorpromazine.[24]

findings is unknown, although a phase advance of Whether patients develop a partial tolerance tothe circadian rhythm of other hormones is recog- the pituitary effect of antipsychotics after severalnised in several psychiatric disorders, including se- months of treatment is unclear.[33,34] If tolerancerum cortisol and melatonin in depression[22,23] and does occur it is likely to be partial, since patientsmelatonin in schizophrenia.[17]

treated for several years still have significantlyIn summary, in unmedicated patients with acute higher prolactin levels than untreated healthy con-

and chronic major psychiatric disorders, daytime trols.[35,36]

prolactin secretion does not appear to be enhanced.Two recent cross-sectional studies from US andIt is therefore reasonable to attribute elevated serum

UK estimated the prevalence of hyperprolactin-prolactin levels in medicated psychiatric patients toaemia in clinically representative samples of pa-drug effects rather than to the illness itself. Confir-tients receiving antipsychotics.[37,38] The cross-sec-mation is provided by longitudinal studies in whichtional study from the US assessed 402 inpatients andprolactin concentration is measured during anti-outpatients with schizophrenia, schizophreniformpsychotic treatment with baseline measurementsdisorder or schizoaffective disorder who had beenbefore the initiation of treatment and/or measure-prescribed a conventional antipsychotic or risper-ments after the antipsychotic drug has been with-idone for at least 3 months.[37] Patients taking con-drawn or switched.comitant medications known to raise prolactin wereexcluded. The prevalence of hyperprolactinaemia in

2.2 Conventional Antipsychoticsmen (>18.77 µg/L) was 42.4% and in women(>24.20 µg/L) was 59.2%. The cross-sectional studySome data suggest that patients with schizo-from the UK assessed 101 patients prescribed con-phrenia show a smaller and slower prolactin res-ventional antipsychotics and found similar re-ponse to a single dose of intravenous haloperidolsults.[38] The prevalence of hyperprolactinaemiathan healthy controls.[19] This implies that schizo-(>480 IU/L) in men was 34% and in women it wasphrenia involves some abnormality in the relation-75%.ship between dopamine and prolactin. Irrespective

of this, both healthy individuals[19] and patients with When oral antipsychotics are discontinued pro-schizophrenia[19,24] show prolactin elevation within lactin levels usually fall to normal within 48–96minutes to hours of starting treatment with conven- hours.[39] However, prolactin levels may take up to 3tional antipsychotics. Prospective studies with an weeks to return to the normal range, depending onopen-label or double-blind design indicate that me- the half-life of the drug and its metabolites as well asdium-term treatment (3–9 weeks) with therapeutic storage in fatty tissues.[40] In the case of oil-based


2296 Haddad & Wieck

depot antipsychotics it may take as long as 6 months (1000 mg/day) and oral flupentixol (25 mg/day) onafter stoppage of the depot preparation for serum serum prolactin levels in a mixed-sex sampleprolactin levels to normalise.[41] (n = 32). All participants had schizophrenia and had

been free of oral antipsychotics for at least 4 weeks2.3 Atypical Antipsychotics and depot antipsychotics for at least 3 months before

entry into the study. After 4 weeks of treatment,Atypical antipsychotics are generally defined as mean serum prolactin levels were significantly ele-

agents that cause minimal extrapyramidal symptoms vated in both groups, in the amisulpride group by a(EPS) at therapeutic doses. Eight commercially factor of 10 and in the flupentixol group by a factoravailable drugs are generally regarded as atypicals: of 5. In female patients the difference in serumamisulpride, aripiprazole, clozapine, olanzapine, prolactin levels between amisulpride and flupentixolquetiapine, risperidone, ziprasidone and zotepine. A

treatment was statistically significant (p < 0.05).number of other agents are in development.

Kleinberg et al.[47] pooled the data of two largeThe term ‘atypical’ should not obscure the factrandomised, double-blind, controlled clinical trialsthat the agents within this class show major differ-comparing 8 weeks of treatment with fixed dailyences in:doses of risperidone (1, 2, 4, 6, 8, 10, 12 and 16mg),• chemical structurehaloperidol (10 and 20mg) and placebo. Both risper-• pharmacodynamicsidone and haloperidol produced dose-related in-• pharmacokineticscreases in plasma prolactin levels in men and• adverse effect profileswomen. The mean increase at endpoint in women• efficacy (clozapine is associated with significant-treated with risperidone was significantly higher

ly greater efficacy in treatment-resistant schizo-than in women treated with 10mg, but not 20mg,

phrenia than the other atypical antipsychotics).haloperidol. In a naturalistic cross-sectional study of

The different propensity of the atypical antipsy-patients with schizophrenia the prevalence of hyper-

chotics to cause hyperprolactinaemia is an excellentprolactinaemia in women (>24.20 µg/L) was higher

example of their differing adverse-effect profiles,among those prescribed risperidone (88%) than

and this may be due to more than one mechanismamong those prescribed a conventional anti-

(section 2.4).psychotic (47.6%).[37]

Clozapine[42] and quetiapine[28,43] do not elevateBreier et al.[48] compared the effects of risper-plasma prolactin levels across their full dose range.

idone and clozapine in 29 patients (male and female)Olanzapine has little effect on prolactin levels and isusing a 6-week double-blind, parallel-group design.generally regarded as prolactin sparing, although atPatients underwent a 2-week period of baselinehigher doses hyperprolactinaemia can occur.[29,44] Influphenazine treatment (20 mg/day) and were thencontrast, risperidone[45] and amisulpride[46] cause aswitched to receive either clozapine (mean dosemarked and sustained increase in serum prolactin404 mg/day) or risperidone (mean dose 6 mg/day).levels in a sizeable proportion of patients. AlthoughAt the end of the baseline fluphenazine treatmentthe division of atypical antipsychotics into ‘prolac-phase plasma prolactin levels were increased abouttin-sparing’ and ‘prolactin-raising’ is useful, such a2-fold above the normal reference range in eachcategorical division is a simplification; in reality onegroup. After switching, levels decreased significant-has a series of drugs whose likelihood of raisingly into the normal reference range in the clozapineprolactin in any individual patient varies on a di-group, whereas they did not change significantly inmension. This is analogous to the likelihood of thesethe risperidone group.drugs causing other adverse effects such as EPS or

weight gain. David et al.[49] reported a double-blind, random-ised clinical trial which compared olanzapineA randomised, double-blind, parallel-group5–20 mg/day, risperidone 4–10 mg/day and halo-study[46] compared the effect of amisulpride



peridol 5–20 mg/day in schizophrenia. There were aripiprazole did not increase prolactin comparedwith placebo, whereas prolactin was significantly21–23 patients in each arm and the study lasted forelevated with risperidone and haloperidol.[57,58]54 weeks. Patients treated with risperidone had sig-

nificantly higher plasma prolactin levels than thosetreated with either olanzapine or haloperidol. 2.4 Reasons for Differential Effect of

Antipsychotics on Prolactin SecretionFurther evidence of the different propensity ofolanzapine and risperidone to raise prolactin level

Various hypotheses have been put forward tocomes from a study by Kim et al.[50] They prospec-

explain the pharmacological basis of ‘atypical’ ac-tively examined the effect of switching from risper-

tion of atypical antipsychotics, that is, antipsychoticidone to olanzapine in 20 female patients with

efficacy combined with low propensity to causeschizophrenia who had symptoms suggestive of

EPS. These include a relative limbic versus striatalraised prolactin (menstrual disturbances, galactor- selectivity for these agents, interactions with neuro-rhoea and/or sexual dysfunction). Patients were transmitter receptors other than D2, and the inter-switched from risperidone to olanzapine over a action at the D2 receptor itself. The last mechanism2-week period and then continued on olanzapine for appears to be particularly relevant to the issue ofa further 8 weeks. Serum prolactin was measured hyperprolactinaemia.every 2 weeks. Sexual and menstrual functions were

The occupancy of anterior pituitary D2 receptorsassessed at baseline and at the endpoint of 10 weeks.

cannot be directly measured in positron emissionDuring the study serum prolactin decreased signifi-

tomography (PET) studies. However, striatal D2cantly (p < 0.01) and this was accompanied by im-receptors have been used as a substitute taking ad-

provements in menstrual functioning and a decreasevantage of the finding that their affinity is, at least in

in sexual adverse effects that the women attributedin vitro and in vivo studies in rats, similar to that of

to antipsychotic medication. Scores on the Positivepituitary D2 receptors.[59] Two studies in patients

and Negative Syndrome Scale significantly de-treated with conventional antipsychotics found that

creased (p < 0.01) during the 10 weeks, indicatinga 50% striatal D2 receptor occupancy was associated

that, in this sample at least, the switch in anti-with a significant increase of hyperprolactin-

psychotic treatment did not cause any worsening ofaemia.[60,61] Another study, in patients with first-

the patients’ psychiatric condition.episode schizophrenia treated with low-dose halo-

Preliminary evidence indicates that zotepine can peridol, reported a threshold occupancy of 72% forcause prolactin elevation in humans after acute and the development of hyperprolactinaemia.[62] In PETlong-term treatment.[51-53] Ziprasidone is not cur- studies most typical antipsychotics produce arently licensed in the UK but is licensed in several 70–90% D2 receptor occupancy in the basal gangliacountries including the US. A randomised clinical at therapeutic doses, suggesting that the thresholdtrial compared ziprasidone at four fixed dosages for hyperprolactinaemia is lower than or similar towith haloperidol 15 mg/day over 4 weeks.[54] Halo- the threshold for a therapeutic response.[63]

peridol was associated with sustained hyperpro- Therapeutic doses of clozapine consistently pro-lactinaemia, whereas ziprasidone was associated on- duce a lower striatal D2 receptor occupancy thanly with transient elevations in prolactin that returned conventional antipsychotics with values ranging be-to normal within the dosage interval. Similar effects tween 16% and 67%.[63,64] Similar values have beenon prolactin have been reported in studies of ziprasi- reported with quetiapine.[65] Risperidone has beendone in healthy volunteers.[55]

associated with higher D2 receptor occupancy thanAripiprazole is the first of a new class of atypical clozapine,[66] whereas results for olanzapine have

antipsychotic characterised by partial agonist ac- been inconsistent with reports of values equal to thattivity at D2 and 5-HT1A receptors.[56] It is also an of risperidone[66] and lower than that of typical anti-antagonist at 5-HT2A receptors.[56] In clinical trials psychotics and risperidone.[67] These striatal neuro-


2298 Haddad & Wieck

imaging data are broadly consistent with the relative 2.5 Other Psychotropic Drugseffects of typical and atypical antipsychotics on

Antidepressants with serotonergic activity, in-prolactin secretion.cluding selective serotonin reuptake inhibitors

Bringing together results from animal and clin- (SSRIs), monoamine oxidase inhibitors and someical studies, Kapur and Seeman[68] suggested that the tricyclic antidepressants, can cause modest eleva-mechanism underlying antipsychotic differences in tions of prolactin levels.[34,71] When they are givenD2 receptor occupancy and adverse-effect profiles is as monotherapy, symptoms of hyperprolactinaemialargely determined by their receptor-binding charac- have been reported but are rare.[71] In patients whoseteristics and half-lives. According to this model, all prolactin secretion is already stimulated by anti-antipsychotics attach themselves with a similar rate psychotic drugs, serotonergic antidepressants haveconstant to the D2 receptor but they differ in how the potential to elevate prolactin levels above the

threshold required to cause symptoms.fast they dissociate from it. A drug with a short half-life and fast dissociation from the D2 receptor

3. High-Risk Groupswould, at therapeutic doses, achieve a reduction indopaminergic activity sufficient for an antipsychotic Although any patient prescribed a prolactin-rais-effect while at the same time allowing some physio- ing antipsychotic is at risk of developing hyperpro-logical activity to take place. In the case of prolac- lactinaemia, research suggests that certain patienttin-sparing atypical antipsychotics it is postulated groups are at higher risk. These include women,that this residual activity is sufficient to avoid EPS particularly during the postnatal period, children andand symptomatic hyperprolactinaemia. adolescents.

Most available atypical antipsychotics possess3.1 Womenantagonist action at both 5-HT2 and D2 receptors.

Given that 5-HT2 receptor stimulation can cause It has consistently been shown that women haveprolactin release, it has been suggested that the significantly greater prolactin elevations than men5-HT2 receptor antagonism of atypical antipsychot- during long-term treatment with the same anti-ics may counteract the prolactin-elevating tendency psychotic dose.[20,72]

incurred as a result of their D2 receptor antagonism.However, it is unlikely that this mechanism is rele- 3.2 The Postnatal Periodvant. First, persistent prolactin elevation may occur

During pregnancy serum prolactin levels riseonly at pharmacological levels of 5-HT2 receptorseveral-fold.[73] If women do not breast-feed, prolac-stimulation;[69] that is, it may not be a physiological-tin levels usually fall to pre-pregnancy levels withinly relevant control mechanism for sustained prolac-3 weeks of childbirth but in breast-feeding womentin release. Second, some atypical antipsychotics,prolactin levels remain elevated for several months.

such as risperidone, cause hyperprolactinaemia de-Some data suggest that postnatal mothers are partic-

spite being 5-HT2 receptor antagonists.ularly sensitive to the prolactin-elevating effect of

The ability of antipsychotics to pass the blood- antipsychotics. Goode et al.[74] compared prolactinbrain barrier may also contribute to their different levels in six nonlactating psychiatric patients withinpropensity to cause hyperprolactinaemia. The pitui- 6 months of childbirth and 11 female psychiatrictary gland lies outside the blood-brain barrier, and patients who had never been pregnant. Prolactinone would expect that drugs with poor brain pene- levels were measured before and after treatmenttrability and higher serum concentrations, such as with the same antipsychotic medication adminis-sulpiride,[70] would have a greater effect on pituitary tered for at least 1 week. The antipsychotic-inducedprolactin secretion. However, this has, to our know- increase in prolactin levels was greater in the post-ledge, not been systematically investigated. natal women than the nonpuerperal group.



3.3 Children and Adolescents 4. Symptoms of Hyperprolactinaemia

Hyperprolactinaemia can cause a wide range ofPreliminary data suggest that children and ado- clinical symptoms:

lescents may be particularly sensitive to the prolac- • gynaecomastiatin-raising effect of antipsychotics. Wudarsky et • galactorrhoeaal.[75] reported on 35 children and adolescents with • infertilityearly-onset psychosis (mean age 14 years, range

• menstrual irregularities: oligomenorrhoea, ame-9–19 years) who were recruited for several anti- norrhoeapsychotic drug trials involving clozapine, haloperi- • sexual dysfunction: decreased libido, impaireddol or olanzapine. Serum prolactin levels were mea- arousal, impaired orgasm, andsured at baseline after a 3-week washout period and • acne and hirsutism in women (due to relativeafter 6 weeks of treatment. Mean prolactin levels androgen excess compared with low estrogenwere elevated on all three drugs. Prolactin was levels).raised above the upper limit of normal in all ten There is great individual variation in the plasmapatients prescribed haloperidol (100%), in seven of prolactin level at which symptoms appear. Somethe ten olanzapine-treated patients (70%) and in symptoms, for example galactorrhoea, reflect raisednone of the 15 patients prescribed clozapine (0%). prolactin acting on target tissues while other symp-These results are limited by the small samples but toms, for example amenorrhoea, are due to secon-suggest that paediatric patients may show greater dary hypogonadism. Chronic gonadal under-func-prolactin elevations in response to both haloperidol tion may also have long-term health effects whichand olanzapine than adult patients. In contrast, in an are initially asymptomatic. Of particular note is de-8-week study in 15 adolescents with psychotic dis- creased BMD, which may lead to an increased riskorders quetiapine (final average dose 467 mg/day) of osteoporosis, and a possible increased risk ofdid not cause any elevation of prolactin.[76] breast cancer. These issues are discussed in sections

5 and 6.A crucial question is how often antipsychotic-3.4 Other High-Risk Groups

induced hyperprolactinaemia causes hypogonadismin men and women. In women it appears common.

Women of reproductive age may be more suscep- For example, in a recent cross-sectional survey,tible to developing antipsychotic-induced hyperpro- 31.6% of premenopausal women with anti-lactinaemia than postmenopausal women. In a psychotic-induced hyperprolactinaemia had estradi-cross-sectional study of 147 women prescribed con- ol levels typical of those seen in postmenopausalventional antipsychotics or risperidone, the preva- women.[37] In another cross-sectional study oflence of hyperprolactinaemia among the 90 preme- women prescribed conventional antipsychotics, pro-nopausal women was 65.6% (mean serum prolactin lactin levels were significantly negatively associated69.0 µg/L), whereas among the 51 postmenopausal with sex hormone levels (p < 0.05) and more thanwomen it was 45.1% (mean serum prolactin 50% of the women were hypogonadal.[32] There are49.0 µg/L).[37] However, this difference may reflect fewer data on the prevalence of hypogonadism infactors other than menopausal status, for example men prescribed antipsychotics. In a recent study theantipsychotic drug and dosage. This study[37] also mean testosterone level in male patients prescribedfound that non-Caucasian women had a higher prev- conventional antipsychotics was within the normalalence of hyperprolactinaemia than Caucasian range.[32] However, this may reflect the fact that thewomen, but again this may reflect differences be- mean prolactin level in these men was also withintween the two groups in terms of antipsychotic drug the normal range, which in turn may reflect theand dosage. relatively low mean dose of antipsychotic med-


2300 Haddad & Wieck

ication that was prescribed. In another study of 56 Research suggests that health professionals oftenfail to detect antipsychotic-induced hyperprolactin-male schizophrenic patients receiving antipsychoticaemic symptoms.[2] There are several reasons fordrugs the mean serum prolactin level was elevatedthis, including the nature of the symptoms and thebut the mean serum testosterone level remainedattitudes of both patients and health professionals.within normal limits.[77] In the largest cross-section-Some patients and professionals may be embarassedal study to date of 255 men treated with convention-to discuss endocrine and sexual symptoms. Patientsal antipsychotics or risperidone, hyperprolactin-who do not associate these symptoms with anti-aemia was associated with significantly lower tes-psychotic treatment are unlikely to volunteer theirtosterone levels.[37] In summary, hypogonadismpresence to psychiatric staff. If health professionalsappears common in female patients receiving anti-are unaware of the symptoms of hyperprolactin-psychotics, though this may be partly due to illness-aemia they will be unable to screen for their pres-related factors rather than antipsychotic-inducedence or recognise their relevance if patients com-hyperprolactinaemia alone (section 4.5). The preva-plain of them. Finally, unlike some antipsychoticlence, and hence clinical relevance, of anti-adverse effects (e.g. extrapyramidal symptoms andpsychotic-induced hypogonadism in men has beenweight gain), symptoms of hyperprolactinaemia are

less often investigated.not visibly stigmatising and this reduces the likeli-

Long-term elevation of prolactin levels may have hood of their detection.a number of as yet unknown physical effects. Bind-ing sites for prolactin are widely distributed in the 4.1 Gynaecomastia and Galactorrhoeabody, and several hundred different actions havebeen described, at least in vertebrate animals.[78] For Hyperprolactinaemia can cause gynaecomastia inexample, prolactin is a known immunomodulator men and galactorrhoea in both sexes. Galactorrhoeaand has been linked to tumour growth. However, the is much more common in women than men.[81,82]

clinical significance of these actions has not yet Gynaecomastia is uncommon and can be unilateralor bilateral.[81,83,84] Estimates of the prevalence ofbeen firmly established.galactorrhoea in women treated with conventionalSeveral studies have reported an association ofantipsychotics vary widely from 10% to more thanhyperprolactinaemia with hostility, anxiety and de-50%.[82] These differences partly reflect differencespression, although the severity of these symptomsin methodology including how galactorrhoea is de-appears to be mild.[79,80]

fined. In most women who have given birth, smallDetermining the prevalence of symptomatic amounts of serous fluid can be expressed from one

hyperprolactinaemia raises various methodological or both breasts despite normal prolactin levels, butproblems. It depends on which symptoms are cho- significant milk production usually occurs whensen and how these are defined. Furthermore, a cross- prolactin levels are above the normal referencesectional study can show only an association be- range.[85]

tween symptoms and raised prolactin. Proving a A well conducted study found that 21 of 150causal relationship is more complex. Causality may women (14%) developed galactorrhoea within 75be implied from a close temporal association be- days of commencing typical antipsychotic treat-tween starting an antipsychotic drug and the occur- ment.[82] Another seven women developed galactor-rence of prolactin elevation accompanied by charac- rhoea during antipsychotic treatment in the run-up toteristic symptoms. However, ideally it requires a entering the study, giving a prevalence rate of 19%follow-up study to determine whether reversal of (28 of 150). Only 8 of the 28 women reported thehyperprolactinaemia is accompanied by symptom symptom on their own initiative to their researcherresolution. Few studies have taken account of these or doctor, partly because of its being perceived as aissues. personal experience or as embarrassing.[86] This il-



lustrates that symptomatic hyperprolactinaemia is Investigating the effect of sexual functioning inoften unrecognised. Out of 28 women with galactor- patients with schizophrenia is methodologicallyrhoea 24 women had a serum prolactin estima- complex. Sexual functioning has various facets in-tion.[82] The median value was 37.5 µg/L (range cluding desire/libido, ability to achieve arousal (lu-10.0–246.0 µg/L), and 20 of the 24 women had brication in women, erection in men) and ability tovalues ≥16 µg/L. The incidence of galactorrhoea in achieve orgasm. Each facet can be affected in vari-this study in parous women was approximately ous ways by the illness itself or the drugs used totwice that in nonparous women, suggesting that

treat it, that is, antipsychotic-induced hyperpro-hormonal priming of the mammary gland in the

lactinaemia is only one of several mechanisms thatform of pregnancy increases the risk of galactor-

may contribute to sexual problems (table I). Therhoea.existence of these different mechanisms means thatIn a pooled analysis of two clinical trials compar-in some patients antipsychotic medication may im-ing haloperidol and risperidone the prevalence ofprove sexual functioning compared with that whengalactorrhoea was 2.4% and 2.2%, respectively.[47]

they were psychiatrically ill but untreated, but inHowever, both values are likely to be an underesti-other patients medication may cause a worsening ofmate, as the study population included postmeno-sexual functioning, even if the medication is effec-pausal women, who may be less likely to develop

drug-induced hyperprolactinaemia. Furthermore, it tive in treating their illness.[90]

is not clear whether the data refer to the prevalence Evidence from both medical and psychiatricof these symptoms during the trial or an increase in populations supports an association between hyper-severity compared with the pretrial antipsychotic prolactinaemia and sexual dysfunction, but it is un-medication. Mammary adverse effects of the other

clear to what extent this is due to a direct effect oftwo prolactin-raising antipsychotics, amisulpride

raised prolactin and/or is caused by hypogonadism.and zotepine, have not been systematically studied.Lundberg and Hulter[91] reported that 62.4% of 109women with hypothalamic-pituitary disorders ex-4.2 Sexual Dysfunctionperienced decreased libido. In the subgroup ofwomen with hyperprolactinaemia the incidence wasSexual dysfunction in patients with psychosis is84%, but in those with normal prolactin levels thepoorly researched but existing data suggest that it isincidence was 32.6% (p < 0.001).common and distressing. In a sample of 55 outpa-

tients with schizophrenia treated with antipsychot-ics, Ghadirian et al.[87] reported sexual dysfunctionin 54% of males and 30% of females during treat-ment. Finn et al.[88] reported that patients rated drug-induced sexual dysfunction as more ‘bothersome’than most psychiatric symptoms of their illness. Inanother study of more than 800 patients with schizo-phrenia sexual dysfunction was perceived as a com-mon adverse effect of medication (39% of respon-dents) and was rated second only to weight gain inhow much it bothered patients.[89] In this study sexu-al dysfunction was associated with reduced adher-ence to antipsychotic treatment.[89] This associationheld after confounding variables, including use ofother psychotropic medications and demographicvariables, were considered.

Table I. Cause of sexual dysfunction in patients with schizophrenia

Social impact of illness

Psychiatric symptoms

positive

negative

affective

cognitive

Peripheral and central drug effects

sedation

antidopaminergic activity

anticholinergic activity

antiadrenergic activity

hyperprolactinaemia

Factors unrelated to schizophrenia and its treatment

medical illness

alcohol (ethanol) misuse


2302 Haddad & Wieck

Turning to psychiatric populations, Ghadirian et cantly less impairment of erections and orgasmicfunction than the risperidone group. However, theal.[87] reported that elevated prolactin correlated withlack of prolactin assays in both studies makes itincreasing sexual dysfunction scores in men but notimpossible to comment on whether prolactin ac-women treated with antipsychotics. Two subsequentcounted for the differences between the drug groups.studies of male patients with schizophrenia alsoCase reports have noted improvements in sexualreported higher serum prolactin levels in those withfunctioning when patients with antipsychotic-in-greater sexual dysfunction, although both studiesduced hyperprolactinaemia are switched to pro-had small samples.[92,93] One of the most recentlactin-sparing agents and their prolactin levelstudies in this area was conducted by Smith et al.[38]

normalises.[50,84,96]and involved 101 patients prescribed conventionalantipsychotics. In male patients there was no corre-

4.3 Menstrual Abnormalitieslation between prolactin levels and any measure ofsexual response. However, when analysis was con-

Five cross-sectional studies have investigatedfined to men with hyperprolactinaemia (34% of themenstrual irregularities in women with severe psy-men in the study), prolactin was negatively correlat-chiatric illnesses receiving long-term treatment withed with erectile dysfunction (r = –0.562; p = 0.023)various conventional antipsychotics at therapeuticand quality of orgasm (r = –0.56; p = 0.023), where-doses and found point prevalences of 26%,[97]

as age, depression and autonomic adverse effects40%,[87] 45%,[98] 55%[99] and 78%.[32] However,

were not related. Thus, raised prolactin level ap-these figures need to be interpreted with caution

peared to be the main cause of sexual dysfunction inbecause of small sample sizes (11–40 subjects) and

hyperprolactinaemic men. In female patients prolac-in some studies the absence of a clear definition of

tin level correlated negatively with libido (r = –0.46;what constitutes oligomenorrhoea or amenorrhoea.

p = 0.03) and physical arousal problems such asThe pooled analysis by Kleinberg et al.[47] of data

poor vaginal response (r = 0.52; p = 0.02). Afterfrom two randomised controlled trials of risperidone

controlling for the effect of dose of medication andversus haloperidol has already been referred to in

depression, the association between prolactin levelsection 4.1. In this analysis the prevalence of ame-

and libido became nonsignificant, whereas the asso-norrhoea in women treated with risperidone was

ciation between prolactin level and poor vaginal8%, which was similar to that seen in the haloperidol

response/arousal was strengthened. and placebo groups. However, the data are likely toThere is a paucity of published data on sexual be an underestimate, as 20% of the sample were

dysfunction with atypical antipsychotics. Two stud- taking oral contraceptive medication, and postmen-ies have reported lower rates of sexual dysfunction opausal women were included in the study. Further-with clozapine than with other antipsychotics.[94,95] more, it is not clear whether the data refer to the totalIn a group of 60 men with schizophrenia, Aizenberg prevalence of amenorrhoea or to the onset of ame-et al.[94] reported improved sexual functioning in norrhoea since stopping the pre-trial antipsychoticseveral domains (including desire, ability to achieve medication.orgasm and sexual satisfaction) in those prescribed In a cross-sectional study of 42 women pre-clozapine versus those prescribed conventional anti- scribed risperidone, 48% of those of reproductivepsychotics. Wirshing et al.[95] prospectively com- age experienced abnormal menstrual cycles (secon-pared male patients in three treatment groups: cloza- dary amenorrhoea, oligomenorrhoea or polymenor-pine, risperidone and a combined fluphenazine/halo- rhoea).[37] Nonacs[100] studied 30 premenopausalperidol group. All three groups showed a decrease in psychotic women who were treated over 4 monthssexual dysfunction but the group treated with cloza- with various antipsychotic drugs; 33% developedpine developed significantly less impairment of sex- menstrual irregularities during treatment with ris-ual interest than the other two groups and signifi- peridone and 17% during treatment with conven-



tional antipsychotics. No woman treated with olan- recorded at least one missing menstrual period inzapine developed endocrine symptoms. 73% of women with a diagnosis of schizophrenia

Amisulpride and zotepine are, like risperidone, compared with 12–59% of women with other psy-prolactin-raising antipsychotics. However, we are chiatric diagnoses.[102] However, it is not clearunaware of any published studies of sufficient dura- whether this difference was due to longer hospitaltion that systematically investigated the prevalence admissions in schizophrenic patients.of menstrual irregularities with these agents. In medicated women with an established schizo-

phrenic illness, Bergemann[103] found a high inci-4.4 Infertilitydence of anovulatory cycles as judged by estradiol

If a woman has amenorrhoea or oligomenor- and progesterone measurements in three serum sam-rhoea, she is clearly either infertile or subfertile. ples taken over 3 weeks. Prolactin levels wereHowever, some hyperprolactinaemic women who higher in women treated with conventional antipsy-menstruate with normal frequency may have an chotics but sex steroid levels were also low in thoseincreased number of anovulatory cycles, which may treated with prolactin-sparing atypical antipsychot-also render them subfertile. Some amenorrhoeic ics.women treated with antipsychotics may assume they

These findings could indicate either that in someare infertile and consequently stop using contracep-

women an organic impairment leads to both thetion. If such women are switched to a prolactin-

schizophrenic illness and a disturbance in the neuro-sparing antipsychotic they are likely to regain theirendocrine regulation of ovarian activity, or that theirfertility. If this is not explained to them an unwantedreproductive function might be affected by otherpregnancy may arise. The effect of antipsychoticsmechanisms, such as stress resulting from the ill-and hyperprolactinaemia on male fertility has notness, or indeed an as yet unknown action of antipsy-been investigated systematically.chotics on hypothalamic-pituitary function. Irre-spective of the mechanism, the data suggest that the4.5 Disease-Related Dysfunction of thehypothalamic-pituitary system in schizophrenicHypothalamic-Pituitary-Gonadal Axiswomen is particularly sensitive to further distur-

Recent studies have challenged the view that bances such as hyperprolactinaemia.menstrual irregularities in schizophrenic women are

In order to assess the respective contributions of adue to drug-induced prolactin elevation alone.[101]

pre- or coexisting hypothalamo-pituitary-ovarianPrentice and Deakin[98] investigated 40 schizo-dysfunction, hyperprolactinaemia and other drug ef-phrenic patients of premenopausal age attending afects to hypoestrogenism in schizophrenic women itdepot antipsychotic clinic; 18 (45%) women hadwould be important to prospectively follow-up pa-irregular menses or amenorrhoea. Both the currenttients whose medication is being discontinued ordose of antipsychotic and illness factors, includingswitched to a prolactin-sparing agent. Such studiesage of onset and cognitive impairment, were inde-should include women of premenopausal age, usependently related to menstrual dysfunction. Al-instruments that are designed to elicit these adversethough prolactin levels were higher in the womeneffects, take into account past ovarian activity andwith menstrual disturbances than in the normallycarryover effects of recent antipsychotic usage, andmenstruating patients, the difference did not reachobserve women for several months. There are nosignificance.such systematic studies but there are case reports ofA role for illness-related factors is also supportedamenorrhoeic schizophrenic women who resumedby prevalence figures of menstrual irregularities inmenstruation after their antipsychotic medicationschizophrenic women studied in the pre-neurolepticwas discontinued or switched to a prolactin-sparingera. For example, a retrospective study published inagent.[1,50,84,104]1957 reported that over a 5-year period hospital staff


2304 Haddad & Wieck

5. Effects on Bone Mineral Density (BMD) Of particular relevance to this article is researchon women with hyperprolactinaemia unrelated tomedication; many of these women have prolactin-

5.1 Measurement of BMD secreting tumours. The consensus established bystudies in this population is that reduced BMD

Peak bone mass is normally distributed with the (compared with age-matched controls) occurs invariance being due to differences in genotype and its women with elevated prolactin and amenorrhoea butinteraction with environmental influences during not in women with elevated prolactin and normalgrowth, including weight, gonadal hormone ac- menstrual function.[110,111] In other studies of womentivity, calcium intake, vitamin D levels, nutrition with hyperprolactinaemic amenorrhoea the reduc-and physical activity. Radiologically measured tion in BMD has been shown to correlate withBMD is an index of bone mass and is calculated by estradiol but not prolactin levels[112] and with thedividing mineral content by the area or volume of duration of amenorrhoea.[113] Changes are mostbone scanned. Techniques commonly used are sin- marked in the spinal trabecular bone, where BMDgle- or dual-energy x-ray absorptiometry (DEXA) has been reported to be 20–25% lower than in age-or CT scanning. BMD measurements are usually matched controls, whereas the BMD in the forearm,expressed in units of standard deviations above or which has mostly cortical bone, was decreased bybelow the mean value of young, healthy populations only 5% in the same studies.[113,114] In patients in(the T score) or an age-adjusted mean value (the Z whom prolactin levels and menstrual cycles normal-score). The WHO has proposed two diagnostic ise with treatment, spinal and forearm BMD valuesthresholds.[105] ‘Osteoporosis’ denotes a value for increase but remain significantly lower than that ofBMD that is ≥2.5 standard deviation below the adult age-matched normal women.[114,115]

peak mean and ‘osteopenia’ is a T score that liesIn summary, there is convincing evidence thatbetween –1 and –2.49. It has been estimated that, at

hyperprolactinaemia can cause a reduction in BMDthe most vulnerable sites, the risk of fracture approx-in women and that this is mediated via reducedimately doubles with each standard deviation ofestrogen levels. Hyperprolactinaemia may reducedecrease in age-adjusted mean BMD.[106]

BMD in women through other mechanisms, includ-ing alteration of androgen levels[110,111] and a direct5.2 Effect of Hypogonadism Unrelated toeffect of prolactin on bone, but the supporting evi-Antipsychotics on BMDdence is less than that implicating hypoestrogenism.

In women there is abundant evidence that hy- In comparison to women, there has been lesspoestrogenic states can lead to decreased BMD. The research in men regarding the role of gonadal ster-prevalence of osteoporosis increases dramatically oids in maintaining skeletal integrity. Nevertheless,after the menopause and estrogen is effective in there is evidence that testosterone deficiency canstabilising BMD in postmenopausal osteo- lead to decreased BMD. Men with congenital hy-porosis.[107] The hypoestrogenic state that is asso- pogonadism have significant bone loss and an in-ciated with breast-feeding is associated with a re- creased risk of fractures[116] but this could resultduction in BMD that reverses once breast-feeding from a deficiency of peak bone mass attained duringstops and ‘normal’ endocrine status is re-establish- adolescence. Greenspan et al.[117] investigated 18ed.[108] Women who have a premature menopause men with testosterone deficiency acquired in adult-after ovariectomy show decreased BMD, which is hood (secondary to prolactin-secreting tumours) andprevented by estrogen treatment. Other hypoes- demonstrated a significant loss of both vertebral andtrogenic states associated with decreased BMD in- radial bone density which correlated with the dura-clude anorexia nervosa[109] and deficiency of tion of the disease. A prospective follow-up of 20GnRH.[110] men with hyperprolactinaemic hypogonadism



showed that reversal of hypogonadism, independent may be that antipsychotic-induced weight gain mayof the prolactin level, was associated with an in- have a small protective effect on BMD.crease in bone mass.[118]

5.4 Studies of BMD in Psychiatric PatientsTo summarise, in both men and women hyper-prolactinaemic hypogonadism (unrelated to antipsy-

In patients exposed to antipsychotic medicationchotics) can lead to decreased BMD that can bethe relationship between BMD and prolactin hashalted, or partially reversed, by correcting the hy-been assessed in four studies.[124-127] All four studiespogonadism. Extrapolating from these data, oneassessed BMD at the spine and femoral neck andwould expect that antipsychotic-induced hyperpro-compared the results with age- and sex-related nor-lactinaemia, sufficient to cause hypogonadism,mative data. The first two studies[124,125] used dualcould also result in decreased BMD. This is ofphoton absorptiometry, while Meaney et al.[127] usedconcern for two reasons. First, many psychiatricDEXA, a more accurate technique that has nowpatients commence antipsychotic medication insuperseded photon absorptiometry. Akande et al.[126]

their late teens or early 20s and if they developedused CT scanning and DEXA.hyperprolactinaemic hypogonadism at this age it

Ataya et al.[124] studied ten female psychiatricmay result in a reduced peak bone mass. Secondly,patients (mean age 31 years) who were hyperpro-many patients continue antipsychotic treatment forlactinaemic and had been treated with antipsychoticyears or even decades and chronic hypogonadismdrugs for an average of 10 years. Three patients hadmay lead to premature acceleration of bone loss.long-standing drug-induced amenorrhoea and sevenpatients had oligomenorrhoea. BMD was reduced at

5.3 Non-Endocrine Risk Factors for three sites of the femoral head by 12% but not in theOsteoporosis in Psychiatric Patients spine. BMD correlated positively with a histological

measure of vaginal maturation used as an index ofIn addition to drug-induced gonadal dysfunction the biological effects of estrogens.

there are other factors that can place psychiatric Halbreich et al.[125] assessed 68 male and femalepatients at increased risk of osteoporosis. Patients patients who were treated with antipsychotic, anti-with severe mental illness are two to three times depressant and mood-stabilising medication, eithermore likely to smoke cigarettes than the general alone or in combination. In the 33 female patientspopulation.[119] It has been estimated that smoking BMD values were highly significantly lower in the20 cigarettes a day for several years is associated lumbar spine but not in the femoral neck. Estradiolwith a perimenopausal reduction in BMD of levels were not significantly correlated with BMD5–10%.[120] Patients with severe mental illness also measurements in women at any site. However, thishave a high prevalence of excessive alcohol in- could reflect the fact that the study sample includedtake,[121] which can lead to bone loss.[122] This may pre- and postmenopausal patients, thereby obscur-reflect a direct toxic effect of alcohol on bone tissue ing an effect due to antipsychotics. Within the 33or the secondary consequences of alcohol abuse. male patients BMD was significantly reduced inInadequate dietary calcium and protein intake is both the lumbar region and femoral neck. There wasknown to reduce BMD and may be more common in a significant correlation for men between BMD andchronically ill psychiatric patients. Polydipsia, a both free and total testosterone in the lumbar regionnow less common behaviour among patients with and between BMD and free testosterone at the femo-schizophrenia, can also cause osteopenia due to ral neck. For men, but not women, BMD was nega-excessive renal calcium loss.[123] tively correlated with prolactin in the lumbar spine.

Although it is known that weight loss is asso- Meaney et al.[127] assessed 55 patients who hadciated with bone loss, it is not clear whether obesity received prolactin-raising antipsychotics for over 10counteracts bone loss caused by hypogonadism. It years; 57% of male and 32% of female patients had


2306 Haddad & Wieck

age-relevant reduced BMD measures. Multivariate chotics and then reassessing endocrine status andregression analysis showed that bone loss for the BMD at a later date.whole group was correlated with medication doseand for the male group was inversely correlated with

6. Possible Relationship withtestosterone levels. As the female group was post-Breast Cancermenopausal, the investigators could not investigate

whether there was a relationship between gonadalstatus and BMD. Prolactin is known to increase the incidence of

spontaneously occurring mammary tumours in mi-Akande et al.[126] investigated nine preme-ce[131] and to increase the growth of establishednopausal women with schizophrenia who had anti-carcinogen-induced mammary tumours in rats.[132]

psychotic-induced hyperprolactinaemia and ame-These studies cannot automatically be extrapolatednorrhoea. CT scanning was used to assess BMD into humans, as rodent and human tumours differ inthe radius and has the advantage of allowing inde-various aspects, including hormone responsiveness.pendent assessment of the BMD of the cortical andSeveral epidemiological studies have investigatedtrabecular bone. In contrast, DEXA provides a sin-whether female psychiatric patients receiving treat-gle overall measurement. There was a significantment with antipsychotic drugs have a higher inci-reduction in the density of the trabecular bone, butdence of breast cancer but the results have beennot the cortical bone, of the radius. There was noconflicting.[133-135] However, the most recent study,reduction of BMD in the lumbar spine or the femoraland the strongest methodologically, found that anti-neck and this may be due to the use of DEXA topsychotic dopamine receptor antagonists conferredassess these sites and/or the relatively short durationa small but significant risk of breast cancer.[136] Thisof amenorrhoea in this study (mean duration 2.5study had a retrospective cohort design and com-years).pared women who were exposed to prolactin-raising

Reduced BMD has been reported in patients with antipsychotics with age-matched women who weremajor depression and it is thought that this is due to not. There were more than 50 000 women in eachraised plasma cortisol levels and changes in cyto- group and the total follow-up period was more thankine activity.[128] Although depression is common in 200 000 person-years. Incident cases of breast can-schizophrenia, it is unlikely to contribute to bone cer were identified through a cancer registry, andloss, since it is not associated with alterations in definitive breast cancer surgeries, and adjusted haz-hypothalamic-pituitary-adrenal function in these pa- ard ratios of breast cancer were calculated usingtients.[129,130]

multivariate analysis. Use of antipsychotic dop-The findings of reduced BMD in patients treated amine receptor antagonists was associated with a

with antipsychotics[124-127] are preliminary and suf- 16% increase in breast cancer (adjusted hazard ratiofer from small sample sizes and methodological 1.16; 95% CI 1.07, 1.26) with a dose-response rela-shortcomings. However, they are of concern and tionship between larger cumulative dosages andneed to be followed up in future studies of subjects greater risk. The possibility of a causal link betweenwho have homogeneous diagnoses and psychotropic raised prolactin and breast cancer received furthertreatments and clear histories of prolonged hyper- support, as the researchers also found an increase ofprolactinaemia and gonadal deficiency confirmed breast cancer in women who used prolactin-raisingby hormone measurements. Cross-sectional studies antiemetic dopamine receptor antagonists despitecan show only an association between BMD and these women having a different breast cancer riskendocrine abnormalities. Confirmation of causality profile from that of antipsychotic users. The in-requires intervention studies, for example switching creased risk of breast cancer could not be explainedpatients with demonstrated reduced BMD and by increased surveillance. The investigators con-hyperprolactinaemia to prolactin-sparing antipsy- cluded that antipsychotic dopamine receptor antago-



Causes of hyperprolactinaemia

PhysiologicalLactationPregnancySleepStressSexual activityBreast stimulation

PharmacologicalPsychotropic drugs, e.g. antidepressants (particularly serotonergic agents), conventional antipsychotics, some atypical antipsychoticsAntihypertensive drugs, e.g. methyldopa, reserpine, verapamilAntidopaminergic antiemetics, e.g. metoclopramideHistamine H2 receptor antagonists, e.g. cimetidine, ranitidineHormones, e.g. estrogens (e.g. oral contraceptives), protirelin (thyrotropin- releasing hormone)Miscellaneous: amfetamine (amphetamine), opioids

PathologicalPituitary disease: empty sella syndrome, micro-prolactinomas, macro-prolactinomas and pituitary stalk lesions (prevent dopamine reaching the pituitary)Hypothalamic disease: hypothalamic tumours, hypothalamic sarcoidosis and postencephalitisEndocrine disease: acromegaly, Cushing’s disease, polycystic ovary syndrome and primary hypothyroidismMiscellaneous: chest wall lesions (e.g. trauma, neoplasms), chronic renal failure, cirrhosis/severe liver disease, ectopic production of prolactin (e.g. small-cell bronchial carcinoma) and idiopathic

Fig. 1. Causes of hyperprolactinaemia.

nists may confer a small but significant risk of breast aemia, a serum prolactin level should be obtained.cancer. The findings require replication. Mild-to-moderate elevations should be checked

with a second sample to exclude physiologicalIn theory it is possible that hyperprolactinaemiacould be associated with an increased risk of en- surges above the laboratory’s upper reference value.dometrial carcinoma. Some premenopausal women If hyperprolactinaemia is confirmed, this merelywith drug-induced hyperprolactinaemia are anovu- demonstrates an association between the anti-latory but produce sufficient estradiol to stimulate psychotic drug and hyperprolactinaemia; it does notthe endometrium. This action remains unopposed by prove that the antipsychotic drug is the cause,progesterone normally present in the luteal phase of though the likelihood of this is high. Nevertheless, itthe menstrual cycle. In polycystic ovary syndrome is important for the clinician to consider other poss-this constellation has been reported to lead to en- ible causes of raised prolactin (figure 1). A patientdometrial hyperplasia, which can be a precursor to history, physical examination, pregnancy test, thy-endometrial carcinoma in one-third of cases.[137] roid function test, blood urea and creatinine levelWhether this is of clinical significance in drug- can help determine if other aetiologies are responsi-induced hyperprolactinaemia is not clear, since no ble. The presence of headache and visual field de-corresponding studies have been carried out in this fects is suggestive of a sellar space-occupying le-type of patient. sion, but the absence of these features does not

A minority of human breast cancers is prolactin exclude such pathology.sensitive. Consequently, it seems prudent to avoid A close temporal relationship between the onsetprescribing prolactin-raising antipsychotics in pa- of hyperprolactinaemic symptoms and the datetients with a past history of breast cancer. when the antipsychotic drug was either started or

increased in dose suggests that the drug is responsi-7. Investigations andble. For example, in a study of female patients theDifferential Diagnosismedian time to onset of galactorrhoea was 20 days(range 7–75 days) after commencement of anti-If a patient prescribed an antipsychotic drug pre-

sents with symptoms suggestive of hyperprolactin- psychotic medication.[82] However, symptoms can


2308 Haddad & Wieck

begin after a long period of treatment with a stable • onset of hyperprolactinaemic symptoms shortlyafter starting an antipsychotic or increasing thedose of an antipsychotic.[84] To help clarify thedose;temporal link we recommend that, whenever poss-

• absence of signs and symptoms suggestive of aible, a history of menstrual cycling (duration,sellar space-occupying lesion;amount, and intervals of menstruation) as well as of

• a prolactin level <2000 mU/L;lactation and sexual functioning should be taken• other laboratory tests are normal.before antipsychotic medication is initiated. Fur-

The only way to be sure that hyperprolactinaemiathermore, when prolactin-raising antipsychotics areis drug induced is to stop the drug and for this to beused it is helpful to obtain a pretreatment prolactinfollowed by the prolactin level falling to the normallevel, which one can compare with subsequent sam-range. In some patients hyperprolactinaemic symp-ples if the patient develops symptoms associatedtoms will have led to a decision to stop antipsychoticwith relatively modest hyperprolactinaemia.treatment or to switch to a prolactin-sparing agent.

The degree of prolactin elevation can provideIn these cases the management itself serves to con-

some guide to aetiology. In the absence of preg-firm the diagnosis. However, when stopping or

nancy and breastfeeding, a serum prolactin level of switching the antipsychotic is not feasible, clarifica->4500 mU/L is highly suggestive of a prolacti- tion of the cause of hyperprolactinaemia is stillnoma[138] and concentrations >2500 mU/L suggest a needed. In patients treated with oral antipsychoticsmicro-prolactinoma or a non-functioning (i.e. non- one can consider a diagnostic short-term cessationprolactin-secreting) adenoma.[139] Antipsychotics of medication (72 hours usually suffices) to deter-usually produce moderate prolactin elevation of up mine if the prolactin level falls to near normal levels.to six times the upper limit of the reference range This is not feasible in patients treated with intramus-(i.e. up to approximately 3000 mU/L).[34] However, cular oil-based depot antipsychotics, as prolactinit must be stressed that these are approximate levels can remain elevated for up to 6 months afterguides. Non-prolactin-secreting tumours in the stopping a depot antipsychotic.[41] An alternativehypothalamic-pituitary region may present with rel- approach is magnetic resonance imaging (MRI) ofatively modest prolactin elevations within the range the brain to exclude a space-occupying lesion. Theusually associated with antipsychotic drugs. Fur- sensitivity of MRI for surgically proved microade-thermore, antipsychotics can sometimes elevate se- noma approaches 100%, compared with 50% withrum prolactin to values well above 3000 mU/L. For CT.[141] If there is doubt about the cause of theexample, Pollock and McLaren[140] reported on eight hyperprolactinaemia, the patient should be referredpatients (collected over an 18-month period) who to an endocrinologist.were treated with antipsychotic drugs and had serum

8. Managementprolactin levels within the range 3600–7300 mU/L.Particularly high prolactin levels may occur whenantipsychotic drugs are administered to post-natal 8.1 Is Intervention Warranted?women or when patients receive concomitant treat-

Whether a patient with antipsychotic-inducedment with more than one prolactin-elevating drug.hyperprolactinaemia requires intervention depends

In summary, the following features suggest, but on several factors, which include:do not prove, that an antipsychotic is the cause of • how distressing the patient finds the hyperpro-hyperprolactinaemia: lactinaemic symptoms;• use of an antipsychotic that is well documented to • the duration of secondary amenorrhoea in a

cause hyperprolactinaemia, that is, any conven- premenopausal woman; the risk of a decrease intional agent, amisulpride, risperidone or BMD increases with the duration of amenor-zotepine; rhoea;



• how long treatment with the antipsychotic drug is that menstrual function acts in women. At presentexpected to continue; if treatment is envisaged to there is insufficient evidence to conclusively statebe short term, the patient may be agreeable to that antipsychotic-induced hypogonadism in men istolerating the symptoms; a cause of decreased BMD. If these data do emerge

in future there would be a case for routinely moni-• the degree of benefit that the patient has gainedtoring serum prolactin and testosterone in men pre-from the antipsychotic drug;scribed prolactin-raising antipsychotics.• the risk of a relapse should the antipsychotic be

In summary, the risk-benefit ratio for treatmentsubstantially reduced in dose or switched andof antipsychotic-induced hyperprolactinaemia needshow serious the repercussions of a relapse areto be assessed on an individual patient basis. As alikely to be; the duration of antipsychotic treat-general rule, the patient should be fully involved inment and the patient’s past history will help inthe assessment and discussion about managementestimating these risks.options. However, as with many other clinical is-Given preliminary evidence linking antipsychot-sues, the degree to which this is done must beic-induced hyperprolactinaemia to decreasedtailored to the individual patient, taking account ofBMD,[124-127] we recommend that any woman withtheir mental state, educational level, and how muchhyperprolactinaemia and 12 months’ amenorrhoeainformation and involvement they want.should have BMD measurements. This is in keeping

with guidelines from the Royal College of Physi-cians in England,[106] although these guidelines do 8.2 Treatment Optionsnot mention antipsychotics as a possible cause ofsecondary amenorrhoea. BMD measurements Table II summarises the treatment options avail-should be taken at several sites (e.g. lumbar spine, able for hyperprolactinaemia, the symptoms thatfemoral neck and forearm), as an estimation at one each treatment option is, in theory, effective againstsite can produce misleading results. The results and the main advantages and disadvantages of each.should be incorporated into the assessment of risks A reduction in dose of the offending anti-and benefits of continuing the current antipsychotic. psychotic is the simplest treatment strategy but itsWe recommend that patients with either osteopenia effectiveness is unpredictable and it carries the riskor osteoporosis on one or more sites be referred for of precipitating an exacerbation or relapse ofspecialist advice on further management. psychotic symptoms. Switching the patient to a pro-

Assessing the risk of osteoporosis in male pa- lactin-sparing antipsychotic (i.e. aripiprazole, olan-tients is hindered by the fact that men do not have an zapine, quetiapine or clozapine) usually proves ef-objective indicator of gonadal function in the way fective, though there is also a risk of relapse.[50,84]

Table II. Treatment options for symptomatic antipsychotic-induced hyperprolactinaemia

Treatment Symptoms, against which Advantages Disadvantagestreatment, in theory, is effective

Decrease dose of existing All symptoms of Simple Risk of relapseantipsychotic hyperprolactinaemia Unpredictable effectiveness

Switch to a prolactin-sparing All symptoms of Only method that allows Risk of relapseantipsychotic hyperprolactinaemia confirmation that Inappropriate if compliance is of

hyperprolactinaemia was concern and patient is maintainedcaused by antipsychotic on a long-acting depot injectiona

Dopamine receptor agonist All symptoms of Allows continued treatment with Risk of relapsehyperprolactinaemia existing antipsychotic Dopamine receptor agonist-

induced adverse effects

Combined oral contraceptive Symptoms of estrogen Allows continued treatment with Thromboembolism(females only) deficiency existing antipsychotic Breast cancer

a Prolactin-sparing antipsychotics are not currently available as depots.


2310 Haddad & Wieck

There are sometimes good reasons to continue 9. Conclusions and Future Researchtreatment with a prolactin-elevating antipsychotic.

In men and women treated with conventional andFor example, a long-acting intramuscular depot may

certain atypical antipsychotics hyperprolactinaemiabe the only way to ensure adequate adherence with is common and can lead to a range of symptomsantipsychotic treatment, and the risks of relapse may with important clinical consequences. In spite of thisbe felt to be too high to justify stopping the depot the phenomenon has attracted much less interestantipsychotic (at present prolactin-sparing atypical than extrapyramidal adverse effects. Hyperpro-

lactinaemia should become a focus of interest,antipsychotics are not available as depot injections).particularly given the introduction of prolactin-spar-In such cases a D2 receptor agonist, such as bromo-ing antipsychotics and increasing knowledge aboutcriptine or cabergoline, can be considered. Mostits possible long-term adverse effects.experience relates to using bromocriptine to treat

Several key problems are apparent in the existingsymptomatic hyperprolactinaemia caused by pituita-literature. First, there is a paucity of data reflectingry tumours rather than antipsychotic medication andthe low priority given to this phenomenon. Second,

the outcome seems less effective in the latter group.when effects on prolactin secretion are reported in

Amenorrhoea responds better than galactor- drug trials this is usually in the form of the numberrhoea.[142-145] Dopamine receptor agonists can cause of patients with hyperprolactinaemia, with little orpsychotic relapse, although the risk is fairly small in no attempt to relate it to its clinical manifestations.stable patients taking maintenance antipsychotic Third, the short duration of most randomised con-medication.[145-148] Other adverse effects depend on trolled trials (several weeks) means that it is impos-

sible to identify amenorrhoea or oligomenorrhoea,the agent used; for example, bromocriptine canas these are usually defined as occurring over acause postural hypotension, gastrointestinal symp-period of at least 3 months. Fourth, the existingtoms and vasospasm of the fingers and toes, espe-cross-sectional studies of patients on long-termcially in those with Raynaud’s syndrome.medication can identify only an association between

If there are good clinical reasons for a preme- raised prolactin levels and symptoms. Proving anopausal female patient to remain on a prolactin- causal relationship requires a follow-up study toraising antipsychotic but this is causing amenor- determine whether reversal of hyperprolactinaemiarhoea (i.e. a clinical marker of estrogen deficiency), is accompanied by symptom resolution. Further re-

search is badly needed in this areathe use of combined oral contraceptives should beThe extent to which a latent dysfunction of theconsidered. This will prevent symptoms associated

hypothalamic-pituitary-ovarian axis in women withwith estrogen deficiency, including possible loss ofschizophrenia, and pharmacological effects unrela-BMD, although symptoms directly due to hyperpro-ted to prolactin, contribute to endocrine and sexuallactinaemia (e.g. galactorrhoea) will be unaffected.symptoms needs to be clarified. Future researchThe oral contraceptive is associated with an in-should also address the degree of distress that hyper-

creased risk of thromboembolism and breast can-prolactinaemic symptoms cause and how this may

cer,[149] and these risks should be carefully assessed affect medication compliance in the long term. Fi-and discussed with the patient before commencing nally, the long-term adverse effects of raised prolac-estrogen replacement. In patients with anti- tin and secondary hypoestrogenism are unclear, es-psychotic-induced hyperprolactinaemia, it has been pecially the potential effects on BMD.recommended that prolactin levels are monitored

Acknowledgementsevery 2–3 months for the first 6 months of hormonereplacement therapy, followed by annual measure- Both authors have received lecture fees and conferencements.[150] expenses from the manufacturers of several atypical antipsy-



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