cycles [6]. There is evidence that high responders to ovarian stimulation are more likely to have higher incidence of transient hyperprolactinemia than intermediate or low responders [7]. Furthermore, serum PRL levels during an ART cycle are strongly correlated with peak estradiol levels [7]. However, there is no evidence that oocytes retrieved or fertilized, or the pregnancy rates are affected by transient hyperprolactinemia [6–9]. Such transient hyperprolactinemia during an ART cycle is therefore unlikely to be clinically significant.
Causes of hyperprolactinemia
The causes of hyperprolactinemia can be classified as physiological, pharmacological and pathological [10].
Physiological causes
Pregnancy and lactation are the commonest causes of hyperprolactinemia. Macroprolactin (larger molecular forms of PRL), which has no biological activity or clinical significance, can be detected in some assays [2]. Stress, excessive exercise and convulsions can also result in hyperprolactinemia, as can chest wall/nipple stimulation, even in nonlactating women.
Pharmacological causes
Many medications can cause hyperprolactinemia, predominantly via inhibition of dopamine synthesis or blockade of endogenous dopamine receptors [10,11]. The most common medications to cause hyperprolactinemia are antipsychotics, antidepressants and some antiemetics (Table 14.1).
Pathological causes
Pituitary tumors. Pituitary tumors can cause hyperprolactinemia via two mechanisms; prolactinomas secrete excess PRL, while large nonfunctioning pituitary adenomas can cause pituitary stalk compression, disrupting the communication between the dopaminergic neurons that control PRL secretion and lactotrophs. Pituitary stalk disruption can also occur following pituitary surgery or trauma. Hyperprolactinemia due to pituitary stalk disruption is usually modest, with levels rarely exceeding 150 μg/L (~3000 mIU/L), whereas prolactinomas can be associated with levels > 1000 μg/L (~20000 mIU/L) [12,13].
Renal failure. Hyperprolactinemia can occur in up to 30% of patients with chronic kidney disease, most likely due to decreased renal clearance of PRL or impairment of dopamine’s regulatory action by uremia [14].Table 14.1 Medications which cause hyperprolactinemia [10,11].AntipsychoticsPhenothiazines: chlorpromazine, trifluoperazine, fluphenazine, perphenazineThioxanthenes: thiothixeneButyrophenonesAtypical antipsychotics: risperidone, olanzapine, quetiapine AntidepressantsTricyclic antidepressants: imipramine, amitriptylineMAO inhibitors: tranylcypromineSSRIs: fluoxetine, paroxetine, citalopram, fluvoxamine Gastrointestinal medicationsMetoclopramideDomperidoneCimetidine Antihypertensivesα‐methyldopaReserpineVerapamil Estrogens Opioids
Primary hypothyroidism. Primary hypothyroidism can occasionally cause a mild increase in PRL, mediated primarily by increased secretion of TRH [5].
Polycystic ovary syndrome (PCOS). Early literature documented mild hyperprolactinemia in up to 30% of women with PCOS [15]. However more recent studies have shown a less frequent association of these disorders, with rigorous etiological approaches detecting other causes to account for the hyperprolactinemia [16,17]. These findings suggest hyperprolactinemia found in PCOS is due either to transient increase in serum prolactin levels, macroprolactinemia or other etiologies, and the two conditions are not linked [16,17].
Liver cirrhosis. Hyperprolactinemia has been documented in up to 20% of patients with liver cirrhosis [18]. The precise pathophysiological mechanism is unknown, but hyperprolactinemia in this setting is seen as a marker of poor prognosis [18].
Chest wall lesions and trauma. The precise mechanism for hyperprolactinemia following chest wall trauma remains unclear, but it has been suggested that stimulation of the intercostal nerves from T2 to T6 causes PRL release [19].
Idiopathic hyperprolactinemia. This is when no specific cause of hyperprolactinemia can be identified. Some cases may have a prolactinoma that is too small to be identified by magnetic resonance imaging (MRI) scanning. In others, PRL may return to normal in due course with no specific intervention.
Investigation of hyperprolactinemia
In patients presenting with raised PRL, a detailed medical history and examination will exclude many causes of hyperprolactinemia. It is important to rule out pregnancy, take a detailed drug history and enquire about pressure symptoms such as headaches, visual field defects, or cranial nerve deficits to exclude pituitary pathology [10,14]. A single measurement of PRL in a blood sample obtained at any time of the day is usually adequate to document hyperprolactinemia, although the pulsatile nature of PRL secretion and the effect of stress may result in levels that are just outside the normal range [14]. In this situation, obtaining three blood samples at 20 minute intervals is a practical means of confirming or excluding the diagnosis [13]. All hyperprolactinemic samples should be screened for macroprolactin.
Urea, electrolytes, thyroid‐function, liver‐function and pregnancy tests should all be considered. Where there is history of chest pain or lesion, a chest X‐ray may be helpful. Once other causes of hyperprolactinemia have been excluded, MRI is the investigation of choice for pituitary tumors [10].
Management options
Before ART treatment is commenced, women with hyperprolactinemia should be investigated for known causes, and appropriate treatment to treat any underlying causes and normalize PRL should be undertaken. Where it is thought to be medication‐induced, and if it is possible to do so safely, the medication should be discontinued and PRL repeated 1 week later [11,13].
The primary goal of therapy in patients with hyperprolactinemia is to restore gonadal and sexual function by normalizing PRL levels [13]. If successful, in women of childbearing age fertility is generally restored. Occasionally patients with mild hyperprolactinemia with regular menses who wish to become pregnant may require treatment [13]. If following successful treatment fertility is not restored, ovulation induction with antiestrogens or gonadotropins can be attempted.
The mainstay of treatment of hyperprolactinemia is treatment or removal of the underlying cause. Where it is thought to be medication‐induced, some guidelines suggest discontinuation of the medication for 3 days or substitution of an alternative drug after consulting the patient's physician, followed by repeat measurement of serum prolactin [1]. However, this is based on low quality evidence, and particularly for antipsychotic medication other guidelines do not endorse this course of action [20].
First line treatment of prolactinomas is dopamine agonist therapy, with surgery traditionally reserved for the few patients who are resistant or intolerant to medication or have predominantly cystic tumors [1,13]. There are however calls for the indications for surgical treatment of prolactinomas to be widened [21]. Most tumors shrink quickly following initiation of dopamine agonist therapy, with normalization of PRL levels. Bromocriptine is well established as a safe and effective therapy for hyperprolactinemia. However, up to 12 % of patients are unable to tolerate it due to adverse events which include nausea and dizziness, and 25% are resistant to it [1,22]. Cabergoline is better tolerated than bromocriptine but is not licensed for treatment of hyperprolactinemia to induce pregnancy. There is, however, no evidence that either is associated with adverse maternal–fetal outcomes [23]. An association has been demonstrated between ergot‐derived dopamine agonist use and valvular heart disease in patients treated for Parkinson's disease, mainly when daily doses are above 3 mg [24]; more recently concern has been raised among endocrinologists about the safety of long‐term treatment with drugs like bromocriptine and cabergoline in hyperprolactinemic patients [25]. Although most reports do not show an association between use of dopamine agonists and clinically relevant valvulopathy in this patient group, regulatory bodies worldwide are now recommending regular monitoring