**1. Introduction**

432 Health Management – Different Approaches and Solutions

The Multi-Society Task Force on PVS. (1994a) Medical aspects of the persistent

The Multi-Society Task Force on PVS. (1994b) Medical aspects of the persistent

Young, A. (1982) The Anthropologies of Illness and Sickness. *Annual Review of Anthropology,* 

ISSN 0028-4793

ISSN 0028-4793

Vol.11, (1982), pp. 257-285, ISSN: 0084-6570

vegetative state (1). *N Engl J Med*., Vol.330, No.21, (May 1994), pp. 1499-1508,

vegetative state (2). *N Engl J Med*., Vol.330, No.22, (June 1994), pp. 1572-1579,

Prolactin is a polypeptide hormone originally discovered from the crop glands of pigeons in 1933 (Riddle et al, 1933; Bushe and Pendlebury, 2010), however there was some scepticism that prolactin even existed in humans until the 1970s as human prolactin was considered identical to growth hormone (GH). During the 1970s, the development of radioimmunoassay techniques allowed the isolation of prolactin and its subsequent measurement (Kohen and Wildgust, 2008). Since that time, awareness of the consequences of hyperprolactinaemia in psychiatry has been less than rapid despite clear evidence that many psychotropic agents, in particular antipsychotics, elevate prolactin levels to some degree in many patients. As a result, prolactin monitoring is not commonplace and many clinicians remain unsure of its utility. In part, this may relate to lack of knowledge regarding pathological endpoints caused by hyperprolactinaemia.

In the last decade, however, awareness has begun to emerge of the potential consequences of untreated hyperprolactinaemia including short-term adverse events of sexual dysfunction, amenorrhoea and infertility and longer term consequences that may include bone fractures and breast cancer. This has been due in part to a number of reviews focussing on the potential consequences of hyperprolactinaemia and the relatively high prevalence of this adverse event (Haddad and Wieck, 2004; Bostwick et al, 2009; Bushe and Pendlebury, 2010), ). In 2008 the first set of prolactin monitoring guidelines was published and more recent data have begun to evaluate the use of specific polypharmacy to reduce prolactin levels (Peveler et al, 2008). There remain, however, many unanswered questions; most relate to the need to establish the true incidence of longer term sequelae of hyperprolactinaemia and to the simple question- what level of prolactin actually carries consequences and when? When one considers that prolactin has at least 300 biological actions it may be that this diversity of function will lead to research that further defines the precise role of and subsequent pathology induced by hyperprolactinaemia (Fitzgerald and Dinan, 2008).

#### **2. Prolactin – What do we know about the hormone?**

#### **2.1 Structure and release**

Prolactin, a polypeptide hormone that binds to prolactin receptors, is considered part of the Class 1 cytokine receptor family present in various organs including pancreas, liver, uterus

Prolactin and Schizophrenia, an Evolving Relationship 435

Units of measurement have the potential to cause some confusion as US and EU data are often presented in ng/ml whereas most UK data are in mIU/L. Conversion rates from ng/ml to mIU/L are not standardised and vary between 21.2 and 36 dependent on the assay employed (Bushe et al, 2008). Furthermore, clinical reports do not always report either the

Definitions of hyperprolactinaemia vary depending upon the upper limit of normal (ULN) for the local assay. Normal ranges for females tend often to be around 30% higher than males, with some laboratories also reporting separate ranges for premenopausal and postmenopausal females. In the psychiatric literature, some of the highest ULNs for females are around 700 mIU/L and, for males, 500 mIU/L (Bushe and Shaw 2007), with lowest ULN at 300 mIU/L for females (Meaney et al, 2004). The Maudsley guidelines 10th edition (Taylor et al, 2009) gives fairly specific advice on blood sampling (1 hour after waking or eating) and cites normal ranges in both ng/ml and mIU/L. In their view, the ULN for females is <530 mIU/L and for males is <424 mIU/L; re-testing is advised if the prolactin level is between

There is currently also no specific definition for an elevated prolactin level that may be regarded as clinically non-significant and when we published our original data set there was no specific guidance to either diagnose or grade level of severity of hyperprolactinaemia (Bushe/Shaw 2007). Thus, we created three specific grades of hyperprolactinaemia: slightly elevated (<1000 mIU/L), significant elevation (1001-2000 mIU/L) and severe elevation (>2000mIU/L). This was based on empirical judgement and not with relation to specifically defined outcomes. In general terms, prolactin levels <2000 mIU/L may be due to a medication effect but other causes can include microprolactinoma, pituitary stalk compression, renal failure or hypothyroidism (Holt, 2008). The literature currently reports that macroprolactinomas are the most common cause of prolactin levels >2120 mIU/L in the general population (Bushe et al, 2010) although other authors propose higher levels (3180 mIU/L) at which hyperprolactinaemia can be assumed to be caused by a

When evaluating hyperprolactinaemia it is also critical to understand the incidence or prevalence of hyperprolactinaemia from the patient perspective as opposed to a mean level from a cohort. Recent data are now tending to more commonly include both variables (Mackin et al, 2011) whereas in our 2008 review of this topic we reported that though 60% of studies reporting prolactin data included some degree of categorical analysis, this was seen mainly in the naturalistic studies (88%) rather than the randomised controlled trials (42%)

Many of the longer term definitive outcomes associated with elevated prolactin remain unknown. Recent findings of prolactin receptors in atherosclerotic plaques in coronary arteries of healthy subjects indicate a possible role of prolactin even in coronary artery disease (Reuwer et al, 2009). There are, however, three areas of pathology that would seem to be closely linked to elevated prolactin, sexual function, bone loss and cancer and these

**3. Measurement of prolactin and definition of hyperprolactinaemia** 

normal range utilised or sometimes the units of measurement (McEvoy et al, 2007).

530-2120 mIU/L.

macroprolactinoma (Holt, 2008).

**4. Consequences of hyperprolactinaemia** 

can be considered as short- and longer term potential adverse events.

(Bushe et al, 2008).

and prostate and consequently may have some immunological activity. It is predominantly synthesised and secreted from the lactotroph cells of the anterior pituitary (Fitzgerald and Dinan, 2008). Lactotrophs form around 20-50% of the cellular population of the pituitary with those in the more inner zones being more responsive to dopamine. Structurally, prolactin is a single chain of 199 amino-acids containing six cysteine residues and three disulfide bonds with 40% homology between the genes encoding prolactin and GH (Fitzgerald and Dinan, 2008).

Prolactin is released from the anterior pituitary in a pulsatile manner and has a half life of around 50 minutes (Citrome, 2008). It peaks around 10 times per day in young adults (Holt, 2008) with a marked circadian rhythm highest during sleep and reaching a nadir during waking hours. Time of measurement is thus important to standardise and is best undertaken before drug dosing in a fasting state in the morning, although this is not always pragmatic in schizophrenia due to the nature of the illness. Measurement of levels during the day needs to be relatively precise as stress factors, exercise and eating can alter levels. In addition, there appears to be an annual circadian variation though with little clinical relevance. Garde et al (2000) reported that prolactin was highest in healthy female subjects in March-May (153 mIU/L) and lowest in September-November (98 mIU/L) (Garde et al, 2000).

Increasingly other confounding factors are being recognised that potentially also affect prolactin levels and any clinical interpretation of abnormality. For example, fluctuating prolactin levels have been found to be greater over the 24-hour period after dosing with perospirone than with either risperidone or olanzapine, despite the magnitude of hyperprolactinaemia being greater with risperidone (Yasui-Furukori et al, 2010). Recent data are supportive of current smokers taking antipsychotics having both a lower mean prolactin level (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.2-4.7, p=0.002) and a lower prevalence of hyperprolactinaemia (Mackin et al, 2010) and other data are supportive at a minimum that is true in females (Ohta et al, 2011). This may be a critical confounder in schizophrenia where almost all patients smoke and indeed smoke more cigarettes than smokers in the general population. Other confounders are much better recognised with a study of 154 schizophrenia patients taking 6mg risperidone reporting that prolactin levels correlate with gender (higher in females), age (lower in older patients) and smoking status (p<0.01) based on a multiple regression analysis (Ohta et al, 2011).

Control of prolactin secretion from the anterior pituitary is predominantly under the control of dopamine released via hypothalamic dopaminergic neurons, the tuberoinfundibular and tuberohypophyseal dopaminergic neurones (Holt, 2008). Dopamine is transported from the hypothalamus to the anterior pituitary via the long hypophyseal portal vessels and inhibits the high basal secretory tone of the lactotroph. This high basal secretory activity is unique amongst endocrine cells. The released prolactin regulates the dopamine synthesis from the hypothalamus via a feedback loop.

The mechanism whereby prolactin is elevated by D2 blockade remains undetermined. However, the most likely explanations relate to speed of D2 dissociation and the ability of the antipsychotic to cross the blood brain barrier (Bushe et al, 2010), with drugs dissociating slowly being associated with greater prolactin elevation. In contrast, quetiapine, an example of an antipsychotic with fast dissociation, has low rates of prolactin elevation being associated with central D2 occupancy that falls from initial blockade of 60-70% at 2 hours post-dosing to around 30% at 24 hours.

and prostate and consequently may have some immunological activity. It is predominantly synthesised and secreted from the lactotroph cells of the anterior pituitary (Fitzgerald and Dinan, 2008). Lactotrophs form around 20-50% of the cellular population of the pituitary with those in the more inner zones being more responsive to dopamine. Structurally, prolactin is a single chain of 199 amino-acids containing six cysteine residues and three disulfide bonds with 40% homology between the genes encoding prolactin and GH

Prolactin is released from the anterior pituitary in a pulsatile manner and has a half life of around 50 minutes (Citrome, 2008). It peaks around 10 times per day in young adults (Holt, 2008) with a marked circadian rhythm highest during sleep and reaching a nadir during waking hours. Time of measurement is thus important to standardise and is best undertaken before drug dosing in a fasting state in the morning, although this is not always pragmatic in schizophrenia due to the nature of the illness. Measurement of levels during the day needs to be relatively precise as stress factors, exercise and eating can alter levels. In addition, there appears to be an annual circadian variation though with little clinical relevance. Garde et al (2000) reported that prolactin was highest in healthy female subjects in March-May (153 mIU/L) and lowest in September-November (98 mIU/L) (Garde et al,

Increasingly other confounding factors are being recognised that potentially also affect prolactin levels and any clinical interpretation of abnormality. For example, fluctuating prolactin levels have been found to be greater over the 24-hour period after dosing with perospirone than with either risperidone or olanzapine, despite the magnitude of hyperprolactinaemia being greater with risperidone (Yasui-Furukori et al, 2010). Recent data are supportive of current smokers taking antipsychotics having both a lower mean prolactin level (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.2-4.7, p=0.002) and a lower prevalence of hyperprolactinaemia (Mackin et al, 2010) and other data are supportive at a minimum that is true in females (Ohta et al, 2011). This may be a critical confounder in schizophrenia where almost all patients smoke and indeed smoke more cigarettes than smokers in the general population. Other confounders are much better recognised with a study of 154 schizophrenia patients taking 6mg risperidone reporting that prolactin levels correlate with gender (higher in females), age (lower in older patients) and smoking status

Control of prolactin secretion from the anterior pituitary is predominantly under the control of dopamine released via hypothalamic dopaminergic neurons, the tuberoinfundibular and tuberohypophyseal dopaminergic neurones (Holt, 2008). Dopamine is transported from the hypothalamus to the anterior pituitary via the long hypophyseal portal vessels and inhibits the high basal secretory tone of the lactotroph. This high basal secretory activity is unique amongst endocrine cells. The released prolactin regulates the dopamine synthesis from the

The mechanism whereby prolactin is elevated by D2 blockade remains undetermined. However, the most likely explanations relate to speed of D2 dissociation and the ability of the antipsychotic to cross the blood brain barrier (Bushe et al, 2010), with drugs dissociating slowly being associated with greater prolactin elevation. In contrast, quetiapine, an example of an antipsychotic with fast dissociation, has low rates of prolactin elevation being associated with central D2 occupancy that falls from initial blockade of 60-70% at 2 hours

(p<0.01) based on a multiple regression analysis (Ohta et al, 2011).

hypothalamus via a feedback loop.

post-dosing to around 30% at 24 hours.

(Fitzgerald and Dinan, 2008).

2000).
