Revised: 7 June 2013
Website: May 2001
Prescriber Update No.21:28-32
Medsafe Editorial Team
Dopamine acts on the pituitary as an inhibitor of prolactin secretion. Blockade of dopamine D2 receptors by typical antipsychotics and risperidone can cause hyperprolactinaemia in males and females. Other atypical antipsychotics do not cause sustained hyperprolactinaemia because of their lower affinity for D2 receptors. Symptoms of hyperprolactinaemia include amenorrhoea, galactorrhoea, infertility, loss of libido and erectile dysfunction. Resulting hypogonadism may cause osteoporosis.
Treat symptomatic antipsychotic-induced hyperprolactinaemia by dose reduction or change to an antipsychotic with less effect on prolactin. Also consider endocrinological consultation. Warn women that menstruation and fertility will return as their prolactin levels normalise, therefore contraceptive advice may be needed.
Typical antipsychotics block dopamine inhibition of the pituitary and
cause prolactin rise
Atypical antipsychotics act on serotonin receptors and have a lower incidence of EPS and negative symptoms
Risperidone can cause sustained hyperprolactinaemia
Hyperprolactinaemia results in hypogonadism and may cause osteoporosis
Consider hyperprolactinaemia in a woman presenting with amenorrhoea while taking antipsychotics
Consider changing the antipsychotic in symptomatic hyperprolactinaemia
Prolactin is secreted by the pituitary gland. It influences gonadal function in both sexes, initiates and sustains lactation in females, and controls libido in males. Normal prolactin levels are slightly higher in women than men. Physiological rises in prolactin level occur during pregnancy, reaching a maximum at the time of delivery, falling postpartum and rising transiently with each suckling episode. Prolactin levels also rise within an hour after eating and after generalised seizures.1 To accurately measure prolactin, check serum levels fasting or at least one hour after food.
Secretion of prolactin by the pituitary is under inhibitory control via dopamine from the hypothalamus. Interference with dopamine secretion or action leads to an increase in serum prolactin. Some medicines can do this by blocking dopamine's action on the pituitary (e.g. phenothiazines, butyrophenones, metoclopramide, risperidone) or by depleting dopamine (e.g. methyldopa, reserpine).1 Opiates can stimulate prolactin release.2 Other causes of hyperprolactinaemia include diseases of the pituitary (e.g. prolactin secreting pituitary adenomas) or hypothalamus, severe primary hypothyroidism, liver cirrhosis, end stage renal disease, stress, high dose oestrogens and chronic cocaine use.1
Dopamine receptor dysfunction is thought to be part of the pathophysiology of schizophrenia.3 There are four major dopaminergic pathways (mesolimbic, mesocortical, nigrostriatal, tuberoinfundibular) and five types of dopamine receptors (D1-5). D2 receptors are found in all the pathways.
In addition, serotonin receptors are believed to play a role in psychosis.3 Serotonin is a modulator of dopamine; if the 5HT2A serotonin receptor is blocked, this leads to an increase in dopamine concentration. The action of antipsychotics depends on their relative affinities for receptors of dopamine and serotonin.
Typical antipsychotics, such as haloperidol, act by blocking D2 receptors in a non-specific fashion. This results in different effects on the four dopaminergic pathways: in the limbic system, it decreases positive psychotic symptoms; in the tuberoinfundibular system, it causes hyperprolactinaemia; and in the nigrostriatal system, it can result in extrapyramidal symptoms (EPS). The effects on the mesocortical pathway are less clear, and may be a combination of therapeutic benefits and drug-induced 'negative' symptoms.3
The first available atypical antipsychotic was clozapine. Over the last ten years it has been joined by risperidone, olanzapine and quetiapine. Atypical antipsychotics can be defined as "those that are effective against psychotic symptoms with a reduced tendency to induce neurologic movement disorders".4 The definition may be expanded to include efficacy against negative symptoms and a wider spectrum of co-morbid symptoms. A prolactin-sparing effect is sometimes included in the definition, but risperidone would then be excluded.
Atypical antipsychotics have a higher affinity for 5HT2A compared to D2 receptors. Clozapine, olanzapine, and quetiapine also show "limbic-specific" D2 receptor binding,3 and hence treat psychosis with less of the negative side effects of dopamine blockade on the other dopamine pathways. Furthermore, serotonin blockade in the nigrostriatal pathways will increase dopamine and thus lower the incidence of EPS.
In contrast to the other atypicals, treatment with risperidone can result in a sustained elevated prolactin level. It causes a rapid5, dose-dependent rise in prolactin3 similar to that observed with haloperidol.6 However, an analysis of randomised double-blind studies of risperidone found the level of prolactin did not correlate with the incidence of clinically detected prolactin-related adverse effects in either sex at usual doses.6 Sustained hyperprolactinaemia is less frequent with the other atypicals. Although olanzapine causes an early dose-related rise in prolactin, this is less frequent and less marked than that seen with haloperidol, and is usually transient.7 A rise in prolactin is seen in about half of patients on olanzapine compared to over 90% of those taking risperidone, and enduring increases were less frequent in those taking olanzapine.8
Why the difference? Risperidone has a high affinity for D2 as well as serotonin receptors.3 It is not "limbic specific" for the mesolimbic over the nigrostriatal tract like the other atypicals.9 Risperidone antagonises dopamine in the tuberoinfundibular system causing a rise in prolactin. However, its antagonist action at 5HT,sub>2A receptors in the nigrostriatal pathways may partially explain why risperidone has a low propensity to cause EPS despite its blockade of D2 receptors.
Hyperprolactinaemia is associated with hypogonadism due to inhibition of hypothalamic release of LHRH. The resulting low levels of oestrogen and testosterone may have long-term consequences. Some advocate screening for hyperprolactinaemia in all antipsychotic treated patients.
In premenopausal women, high prolactin will lower oestrogen levels. This may contribute to the development of reduced bone mineral density, although a causal association between antipsychotics and osteoporosis has not been established.10 Menopausal women may need to be assessed for hormone replacement therapy (HRT), however this will need to be weighed up against the risks of HRT, such as venous thromboembolism in a group among whom smoking and obesity are common. High prolactin may also cause male hypogonadism through lowering of testosterone levels. Testosterone in men is important for improving lean body mass and reducing fat mass.6 When prescribing antipsychotics, consider the significance of other risk factors for osteoporosis such as age, menopause, glucocorticoid use, hyperthyroidism, calcium imbalance, polydipsia, alcoholism, smoking, amenorrhoea, anorexia nervosa, use of medicines such as lithium, dietary deficiency, lack of sun, and immobility.11
There has also been concern regarding hyperprolactinaemia and an increased risk of breast cancer. Although there is evidence in in vitro and animal studies, there are no supporting human data.6,9
In any woman presenting with secondary amenorrhoea on antipsychotics, hyperprolactinaemia must be considered in the differential diagnosis (remember to exclude pregnancy). Women with hyperprolactinaemia may present with irregular menses, galactorrhoea, decreased libido and even infertility despite regular menses. Men may present with reduction in libido, impotence, infertility, and rarely galactorrhoea and gynaecomastia. Other causes of hyperprolactinaemia should be investigated if the prolactin level is raised. The patient should be examined for chest wall irritation (which can promote galactorrhoea and raise prolactin), signs of a sellar mass (including assessment of visual fields), and blood tests done for TSH12 (exclude hypothyroidism) and creatinine (exclude renal failure as a cause of hyperprolactinaemia). Referral for CT or MRI or an endocrinology consultation may be considered.
Treatment of symptomatic hyperprolactinaemia in a patient on antipsychotics firstly involves exclusion of other aetiologies, followed by consideration of a change of medication to a prolactin-sparing antipsychotic or reduction in dose if the patient's mental state is stable. If this proves difficult, then an endocrinologist should be consulted and the risks and benefits of hormone replacement considered. Monitoring the patient's psychiatric status closely is essential if changing regimens. Asymptomatic hyperprolactinaemia in itself should not be an indication for changes to medication.
For all treatment changes, women must be warned that menses may resume along with fertility. Contraceptive advice may need to be given. With the resumption of normal cycles, there is also the risk that premenstrual exacerbation of schizophrenic symptoms may occur, requiring doses of antipsychotics to be adjusted over the cycle.
In order to adequately monitor for hyperprolactinaemia, a menstrual history should be taken prior to commencing a premenopausal woman on antipsychotics. When choosing an antipsychotic, it is important to weigh the overall risks and benefits for the individual patient (male or female). The atypical antipsychotics, while having a better side effect profile than the older agents, still carry a significant burden of treatment which varies between the atypicals. Attention has been drawn to some of these in recent Prescriber Update articles.13,14