**4.1 Short term consequences of hyperprolactinaemia**

#### **4.1.1 Sexual function**

Sex hormone dysregulation may be the underlying cause of both acute and longer term adverse events associated with hyperprolactinaemia as prolactin has a significant effect on sex hormone regulation and prolactin levels in patients treated with antipsychotics are inversely related to steroid sex hormone concentrations (Smith, 2002). However, the absolute link between prolactin and sexual dysfunction is complex. The relative short-term consequences of hyperprolactinaemia are well described and, in addition, to sexual dysfunction include menstrual disturbances, acne, infertility, galactorheoa and gynaecomastia although prevalence rates were until recently not well reported. In 2011, the European First Episode Schizophrenia Trial (EUFEST) study of first episode schizophrenia patients reported that sexual dysfunction was very common at baseline (Malik et al, 2011) and although often attributed to antipsychotics this is not the complete picture as smoking, physical illness, depressive and negative symptoms may also be relevant (Malik et al, 2011). Over the 1-year study, changes in prevalence of sexual dysfunction were small and varied little between antipsychotics despite hyperprolactinaemia being very common and moderately severe (Kahn et al, 2008). The authors concluded that their data emphasized that schizophrenia the illness was a key influence on sexual dysfunction although hyperprolactinemia undoubtedly plays an additional role (Malik et al, 2011). There is also an important investigational aspect to consider. In most antipsychotic studies previous medication prior to study entry is either inadequately or incompletely described, which makes interpretation of variables such as prolactin and sexual dysfunction complex. It is possible that changes measured during the trial may relate to the removal of a previous antipsychotic. As such the only data that can give a true baseline are data in treatment-naïve subjects from studies such as EUFEST. Not all data, however, are consistent with this view that prolactin may play a smaller role in sexual dysfunction than expected (Knegtering et al, 2008). For example, in a 6-week, open label study including 264 patients treated with antipsychotics, prolactin-raising antipsychotics were linked with significantly more sexualrelated adverse events than patients treated with prolactin-sparing antipsychotics. The authors concluded that around 40% of emerging sexual adverse events in schizophrenia are attributable to prolactin (Knegtering et al, 2008). The importance of seeking overt symptomatology however is that it offers the opportunity to measure prolactin as many guidelines have previously not suggested prolactin measurements until the presence of relevant symptoms. The literature is fairly conclusive that sexual dysfunction is not always regarded as an important aspect to discuss with patients in routine clinical practice.

#### **4.2 Longer term consequences of hyperprolactinaemia 4.2.1 Bone**

Data on hyperprolactinaemia and bone loss have appeared during the last decade predominantly due to the work of Veronica O'Keane. Her group systematically followed the link between hyperprolactinaemia and sex hormones (males and females) and then between hyperprolactinaemia and bone loss. Some studies suggest that even relatively short periods of hyperprolactinaemia can have significant adverse effects on bone density (Meaney and O'Keane, 2007; O'Keane, 2008). Young women may be particularly susceptible to hyperprolactinaemia, and osteoporosis and osteopenia may develop in the first 8 years of antipsychotic treatment (Meaney and O'Keane, 2007; O'Keane, 2008). Of more concern is

Sex hormone dysregulation may be the underlying cause of both acute and longer term adverse events associated with hyperprolactinaemia as prolactin has a significant effect on sex hormone regulation and prolactin levels in patients treated with antipsychotics are inversely related to steroid sex hormone concentrations (Smith, 2002). However, the absolute link between prolactin and sexual dysfunction is complex. The relative short-term consequences of hyperprolactinaemia are well described and, in addition, to sexual dysfunction include menstrual disturbances, acne, infertility, galactorheoa and gynaecomastia although prevalence rates were until recently not well reported. In 2011, the European First Episode Schizophrenia Trial (EUFEST) study of first episode schizophrenia patients reported that sexual dysfunction was very common at baseline (Malik et al, 2011) and although often attributed to antipsychotics this is not the complete picture as smoking, physical illness, depressive and negative symptoms may also be relevant (Malik et al, 2011). Over the 1-year study, changes in prevalence of sexual dysfunction were small and varied little between antipsychotics despite hyperprolactinaemia being very common and moderately severe (Kahn et al, 2008). The authors concluded that their data emphasized that schizophrenia the illness was a key influence on sexual dysfunction although hyperprolactinemia undoubtedly plays an additional role (Malik et al, 2011). There is also an important investigational aspect to consider. In most antipsychotic studies previous medication prior to study entry is either inadequately or incompletely described, which makes interpretation of variables such as prolactin and sexual dysfunction complex. It is possible that changes measured during the trial may relate to the removal of a previous antipsychotic. As such the only data that can give a true baseline are data in treatment-naïve subjects from studies such as EUFEST. Not all data, however, are consistent with this view that prolactin may play a smaller role in sexual dysfunction than expected (Knegtering et al, 2008). For example, in a 6-week, open label study including 264 patients treated with antipsychotics, prolactin-raising antipsychotics were linked with significantly more sexualrelated adverse events than patients treated with prolactin-sparing antipsychotics. The authors concluded that around 40% of emerging sexual adverse events in schizophrenia are attributable to prolactin (Knegtering et al, 2008). The importance of seeking overt symptomatology however is that it offers the opportunity to measure prolactin as many guidelines have previously not suggested prolactin measurements until the presence of relevant symptoms. The literature is fairly conclusive that sexual dysfunction is not always

regarded as an important aspect to discuss with patients in routine clinical practice.

Data on hyperprolactinaemia and bone loss have appeared during the last decade predominantly due to the work of Veronica O'Keane. Her group systematically followed the link between hyperprolactinaemia and sex hormones (males and females) and then between hyperprolactinaemia and bone loss. Some studies suggest that even relatively short periods of hyperprolactinaemia can have significant adverse effects on bone density (Meaney and O'Keane, 2007; O'Keane, 2008). Young women may be particularly susceptible to hyperprolactinaemia, and osteoporosis and osteopenia may develop in the first 8 years of antipsychotic treatment (Meaney and O'Keane, 2007; O'Keane, 2008). Of more concern is

**4.2 Longer term consequences of hyperprolactinaemia** 

**4.2.1 Bone** 

**4.1 Short term consequences of hyperprolactinaemia** 

**4.1.1 Sexual function** 

the finding that deterioration can be measured over a single year and essentially cannot be prevented (Meaney and O'Keane, 2007; O'Keane, 2008). A second set of key epidemiological studies evaluating fractures in large UK cohorts was published suggesting that hip and other bone fractures are a sequelae of mental illness and its treatment. Howard reported that hyperprolactinaemia and prolactin-elevating antipsychotics have been associated with a doubling of the risk of hip fracture in schizophrenia patients in a large UK study (OR 2.6, CI 2.43-2.78) (Howard et al, 2007). A second study also using the UK General Practice Research Database (GPRD) reported that in women the highest relative risk of fracture in a mentally ill population were in the youngest cohorts, whereas in males the greatest risks were seen in older age (Abel et al, 2008). The results showed that the relative risk (RR) of any fracture was increased more than double in females with psychotic disorders (RR 2.5: CI 1.5-4.3) but that even greater risk was measured in the cohort aged 45-74 years with psychotic disorders, with a relative risk in women of RR 5.1 (CI 2.7-9.6) and in males RR 6.4 (CI 2.6-16.1) when looking specifically at hip fractures (Abel et al, 2008). This risk may be seen to an even greater extent in males than females (Howard et al, 2007) and is present after adjusting for the other risk factors for osteoporosis highly prevalent in a cohort of patients with severe mental illness (poor diet, low exercise rates, increased alcohol consumption and decreased sunlight exposure). Other data however are needed for other fracture sites ( radius and vertebrae) together with some indication as to whether it is the cumulative length of hyperprolactinaemia that is crucial (a sort of area under the curve measurement) or the effect of a critical peak level of prolactin. Recent data in non-schizophrenic males with prolactinoma reported that using DEXA scanning of the lumbar spine vertebral fractures were diagnosed in 37.5% of patients compared with 7.8% of controls (p<0.001) (Mazziotti et al, 2011) and that these developed independently of hypogonadism.

#### **4.2.2 Possible association with cancer**

A recent systematic review concluded that breast cancer is significantly increased in females with schizophrenia but the data have simply not been published to establish the degree of the putative role of prolactin in this increased risk (Bushe et al, 2009). A number of epidemiological studies have reported data over the last 25 years but it is only in the last few years that clarity has emerged. The importance of systematic review in addressing a clinical question is clear. In this case, when studies with adequate powering and follow up undertaken in an age group where cancer developed (>50 yrs for breast cancer predominantly) are considered, the results were clear. The specific relevance of breast cancer is that it is the most common cancer in women in the UK, it accounts for 23% of all female cancer cases worldwide, there is a lifetime risk of 1 in 9 in the general population and this risk is increasing (Bushe et al, 2010). A recent meta-analysis that included fewer studies than our systematic review (Catts et al, 2008) reported a 12% increased risk (Standardised Incidence Ratio [SIR] 1.12, 95% CI 1.02-1.23) with a more recent UK study reporting an increased risk of 52% in schizophrenia adjusting for recognised confounders such as poverty (Hippisley-Cox et al, 2007). One can only speculate over the role of prolactin and mammary carcinogenesis, however in animal toxicity and molecular studies, it has been recognised over many years (Harvey 2008) that there is a very strong association. The US Nurses' Health Study evaluated prolactin samples from 32,826 patients with normal prolactin levels during the period 1989 to 1990 and these subjects have been extensively followed over 20 years, providing conclusive evidence linking prolactin and breast cancer in the general

Prolactin and Schizophrenia, an Evolving Relationship 439

as low as 500 mIU/L being associated with an increased risk of breast cancer in the general population over the medium term (Tworoger and Hankinson 2006, Tworoger et al, 2007). However, it is critical to understand that whereas there is a strong link between prolactin and breast cancer in the general population, there are no data to address this topic in schizophrenia and bipolar disorder. In addition, breast cancer has very many aetiological factors that include social demographics, education, obesity and family

**6. How common is hyperprolactinaemia in an antipsychotic-treated cohort?** 

There are few cohorts where prolactin levels have been obtained in a complete cohort and rates of hyperprolactinaemia will be dependent on many factors including medication choice, gender, age and length of follow up. Data derived from epidemiological databases is also confounded by selection bias. Without knowing how many subjects were tested there is little way to put perspective around these data (Montgomery et al, 2004). A true perspective requires a complete cohort to be tested. Many other confounders will remain, however, including gender, smoking status, adherence to treatment, age and time on

Olanzapine, for example, may give a transient elevation of prolactin that reduces over the first months in some patients but during chronic administration prolactin elevation may remain (Bushe et al, 2008). Naturalistic data may thus be informative as prolactin monitoring is not routine and prevalence rates in complete populations screened will reflect previous under-diagnosis. Two recent naturalistic analyses in which asymptomatic schizophrenia populations have been screened for prolactin report similar prevalence of hyperprolactinaemia: 38% and 39% in UK (n=194) and Norway (n=106), respectively (Bushe and Shaw 2007; Johnsen et al, 2008). The UK study measured prolactin in the total population of a catchment area in Halifax receiving antipsychotics for schizophrenia or bipolar disorder. The population was clinically asymptomatic prior to the study. Hyperprolactinaemia was more common in females than males (52 vs. 26%), consistent with most other data (Bushe et al, 2008), and significantly elevated levels (>1000 mIU/L) were measured in 21% of subjects. For 13% of females and 19% of males, prolactin levels were above the normal limit but below 1001 mIU/L. Categorical rates of hyperprolactinaemia in trials range from 33 to 69% and confirm that no antipsychotic is prolactin neutral (Bushe et al, 2008). Most studies report both a higher prevalence and severity of hyperprolactinaemia in females as was the case in the Halifax study which found 13% of females had levels >2000

The ideal studies to evaluate prolactin would be a long-term, first episode study where the confounding factor of previous antipsychotic usage would not need addressing and which included multiple treatment arms and a longer term randomised study in chronic schizophrenia. There are few such studies with the exception of EUFEST (Kahn et al, 2008) and CATIE (Lieberman et al, 2005). EUFEST was a 1-year, first episode study and CATIE, an 18-month study with multiple treatment arms. Both these studies concluded that hyperprolactinaemia was common though EUFEST failed to find a direct link between

history and the role of prolactin is simply not known.

mIU/L compared with 2% of males (Bushe and Shaw, 2007).

prolactin and sexual dysfunction.

**6.2 Rates of hyperprolactinaemia with individual antipsychotics** 

**6.1 Overview** 

treatment.

population. Many of their study reports suggest prolactin levels to be linked to the risk of breast cancer development both in pre- and postmenopausal women (Tworoger and Hankinson, 2006; Tworoger et al, 2007). An example of these data found prolactin levels in the upper quartile of normal to be associated with an increased risk compared to the lower quartile of normal (OR 1.34, 95% CI 1.02-1.76) (Tworoger et al, 2007). Any definitive link, however, has yet to be established in schizophrenia and bipolar disorder.

A large retrospective cohort study of 52,819 females receiving antipsychotics and 55,289 control women reported a 16% increased risk of breast cancer (Wang et al, 2002) with a dose response relationship suggesting a greater risk of breast cancer with increased doses of antipsychotic. Regardless of relationship with prolactin, identical breast cancer screening should be encouraged in all schizophrenia subjects as in the general population. Screening rates for schizophrenia patients are very low compared with the general population for an illness that is very common (lifetime prevalence 1 in 9 and rising) and often curable (Bushe et al, 2010).

Hyperprolactinaemia has also been linked to pituitary adenomas and adenocarcinomas and putatively to prostate cancer (Harvey et al, 2008). The US Food and Drug Administration Adverse Event Reporting System pharmacovigilance database study strongly linked risperidone (adjusted reporting ratio 18.7) with the highest frequency of pituitary adenomas compared with haloperidol (5.6), ziprasidone (3.0) and olanzapine (2.3) (Szarfman et al, 2006). A recent case series is suggestive that amisulpride may also be associated with the development of prolactinomas mediated via hyperprolactinaemia (Akkaya et al, 2009).

The multiple actions of prolactin and relative lack of research into hyperprolactinaemia suggest that additional potential long-term effects may be discovered potentially in glands such as the thyroid. Recent data suggest there may be an association with autoimmune thyroiditis and in 75 schizophrenia patients, the prevalence of hyperprolactinaemia was higher in patients with thyroid autoantibodies (p=0.045) (Poyraz et al, 2008).
