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 with echocardiography [26]. Quinagolide is a non‐ergot‐derived agent which is unlikely to cause this side effect and has been used successfully in the management of prolactinomas [22]. Further potential side effects of dopamine agonists include psychological disturbances, either de novo or as exacerbations of prior psychiatric disease. Patients with hyperprolactinemia treated with dopamine agonists need to be warned about and monitored for changes in mood and behavior, impulse control disorders, depression, mania and other types of psychosis [27].
Fertility, pregnancy and prolactinoma
Women with prolactinomas who are pregnant or who wish to become pregnant should be managed with the involvement of an endocrinologist. The main issues which need addressing are hyperprolactinemia and fertility, safety of dopamine agonists, tumor growth and lactation [13].
Hyperprolactinemia and fertility
Ovulation and fertility may be restored immediately following dopamine agonist treatment, even before the first normal menstruation. The couple should be informed about that, and mechanical contraception should be advised if they do not want pregnancy that month [13].
Safety of dopamine agonists
There is considerable worldwide experience with the use of bromocriptine to induce pregnancy and during pregnancy. The incidence of miscarriage, ectopic pregnancies or congenital malformations is no higher in mothers who conceived while taking bromocriptine than in the general population [1,28,29]. Cabergoline has also demonstrated a good safety record, although the number of pregnancies studied is smaller [1,22]. Despite this, it is recommended that dopamine agonists be stopped once the first menstrual period has been missed and a positive pregnancy test is obtained [1].
Tumor growth
The incidence of clinically significant tumor enlargement during pregnancy is < 3% in women with microadenomas (tumors < 1cm in diameter) and approximately 30% in women with macroadenomas (> 1cm in diameter) [1]. Dopamine agonists can therefore be safely stopped in patients with microadenomas as soon as pregnancy has been confirmed, and the patients advised to seek urgent medical attention in the event of severe headaches or visual disturbance [1]. Continuation of dopamine agonist therapy during pregnancy may be considered in cases of macroprolactinoma or where there is evidence of tumor enlargement [1]. If dopamine agonist therapy is discontinued in women with macroprolactinomas, visual‐field testing is recommended in each trimester or more often if necessary. Routine monitoring of PRL levels and MRI should not be performed during pregnancy in patients with prolactinomas, but if visual field defects or progressive headaches develop, a limited MRI without gadolinium can be performed [1].
Lactation
Women wishing to breastfeed should not be given
