FIGURE 9.1 Systematic approach to diagnose the cause of hyperprolactinemia.
The second group of tumors that can induce hyperprolactinemia are tumors that cause mass effects in the sellar region, resulting in a deviation or compression of the pituitary stalk. This will inhibit dopamine from the hypothalamus to reach the PRL-producing cells in the pituitary, in which dopamine decreases PRL secretion. Mass effects generally do not increase prolactin levels above 10 ULN (17). Examples of these macroadenomas (≥1 cm) are non-functioning pituitary adenomas (NFA), secreting pituitary adenomas such as GH, TSH, and, seldomly, corticotropine (ACTH). Tumors from non-pituitary origin are craniopharyngiomas, meningiomas, metastatic lesions, primary brain tumors, germ cell tumors, and infiltrating diseases such as sarcoidosis, histiocystosis, and tuberculosis.
Hyperprolactinemia of more than 10–15 times ULN is almost always caused by a macroprolactinoma (adenoma size ≥1 cm), and MRI evaluation is necessary. In the large pituitary tumors, including prolac-tinomas, there is a risk of developing visual field defects and sometimes the impingement of the optic chiasms that results in a loss in visual acuity. These tumors can even compress other cranial nerves, which can cause eye movement disorders and diplopia.
Treatment Focused on the Most Relevant Pituitary Adenomas Causing Hyperprolactinemia
Non-Functional Adenoma
NFA constitute about 80% of the pituitary adenomas. NFA’s secretory products usually do not cause a clear recognizable syndrome and therefore are called non-functioning adenomas. Patients with an NFA seek medical attention when the adenoma size causes pressure symptoms on surrounding tissues, such as the optic chiasm, and, therefore, give rise to symptoms as headaches, visual field defects, diplopia, and symptoms related to hypopituitarism. However, the tumor mass effects can cause hypogonadism and hyperprolactinemia and mimic a prolactinoma. The treatment of choice for NFA is surgery or, if possible, a wait-and-scan policy and, in some cases, medical treatment with dopamine agonists. However, symptomatic treatment of hyperprolactinemia in NFA can be useful.
Prolactinomas
Lactotroph adenomas are the most common secreting adenomas. Adenoma size and serum PRL levels are generally correlated. Most prolactinoma patients have a PRL level higher than 200 μg/L (10 times ULN). Prolactinomas are almost exclusively treated with primary medical treatment. To date, dopamine agonists are the first line treatment as they usually rapidly normalize PRL levels and reverse galactor-rhea, restore fertility, and also cause tumor shrinkage in most patients (18). In microprolactinomas, treatment is not mandatory because they rarely develop into macroprolactinomas (15,19). However, when patients seek medical attention because of symptoms, such as hypogonadism, infertility, gynecomastia, and galactorrhea, or when there is growth of the microadenoma, medical treatment is indicated. In macroprolactinomas, treatment is almost always mandatory.
In a minority of patients, other treatment modalities should be considered. Examples are prolactinomas that are resistant to dopamine agonist therapy or when the patient does not tolerate medication. In resistant prolactinomas, increasing the dose of dopamine agonists, surgery, and/or radiotherapy can be necessary. The existence of resistance to dopaminergic drugs is empirically defined. The most commonly used definition is a failure to achieve normal PRL serum levels and/or a significant reduction of tumor volume during dopamine agonist treatment (20,21).
Medical Treatment
The lactotroph adenoma cells express dopamine receptors (D1 & D2 subtypes of dopamine receptors). By binding to these D1 & D2 receptors, dopamine agonists, reduce synthesis and secretion of PRL and reduce adenoma cell size (18). In patients, dopamine agonists reduce tumor size and decrease PRL hypersecretion by the lactotroph adenoma in more than 90% of the cases. The decrease in serum PRL levels is generally accompanied by a reduction in tumor size. Within 2–3 weeks after initiation of pharmacological treatment, PRL levels tend to decrease preceding the reduction in adenoma size. After 6 weeks to 6 months of dopamine agonist treatment, a reduction in adenoma size can be observed on MRI (22). In general, the magnitude of decrease in serum prolactin levels correlates well with the decrease in tumor size (13). Finally, during dopamine agonist treatment, the decrease in hyperprolactinemia is accompanied by a reduction in signs and symptoms.
Several dopamine agonists are available for the treatment of hyperprolactinemia and prolactinomas. Depending on the patients’ characteristics, therapeutic expectations, and possible side effects, the most optimal dopamine agonist should be chosen to increase efficacy and patients’ compliance (23). For 30 years, bromocriptine has been used, and it is one of the oldest ergot derivatives currently available. For an optimal therapeutic effect, a twice-daily dose is necessary (24). Once or twice weekly dosing is possible with another ergot dopamine agonist cabergoline. Cabergoline is a more effective medical treatment with a lower tendency to cause nausea than bromocriptine (18,25). An ergot derivative primarily used in high doses of >3 mg/day for the treatment of Parkinson’s disease is pergolide (26). Typical doses in prolactinoma patients range from 0.05 to 1.0 mg/day. Increased risk of valvular heart disease is associated with the use of high doses of pergolide for the treatment of Parkinson’s disease (27). For this reason, pergolide was withdrawn from the U.S. market in 2007. Valvular heart disease is associated with high doses of a specific class of dopamine agonist, the ergot derivatives.
A non-ergot dopamine agonist, quinagolide, is registered for once daily use. The problem is that quina-golide is not available in some countries (28,29).
Efficacy of Dopamine Agonists
Cabergoline seems to be superior to bromocriptine in decreasing serum PRL levels (18). Normalization of PRL levels with an efficacy rate of 80%–90% can be expected during cabergoline treatment. A higher efficacy rate of >95% was observed when patients were up-titrated in cabergoline doses up to weekly 12 mg (30). In most studies, weekly doses over 3.5 mg are relatively rare.
Quinagolide has more or less the same efficacy as cabergoline although a few studies suggest the superiority of cabergoline (29). The great advantage is the non-ergot nature of the drug. This would imply an absence of the increased reported risk of the development of valvular heart disease, which can be seen during high-dose ergot derivate treatment.
Withdrawal of Dopamine Agonists
Remission rates after discontinuation of dopamine agonists differ significantly between studies. For macroadenomas, rates of 16%–64% and, for microadenomas, rates of 21%–69% are reported. In a recent meta-analysis, an average remission rate of 21% for microadenomas and 16% for macroadenomas was reported (31). Higher remission rates were seen in studies in which cabergoline was used, a longer duration of the treatment, and when shrinkage of the adenoma was >50%. The highest probability of remission can be expected when PRL serum levels are normal for a longer period of time and no visible tumor can be seen on MRI for at least 2 years. In general, the remission rates are low, especially in macroprolactinomas. When discontinuation is not feasible, a reduction in the dopamine agonist dose may well be possible without losing biochemical and symptom control.
Adverse Effects
Common side effects of dopamine agonist drugs are orthostatic hypotension, nausea, abdominal discomfort, and mental disturbances. Initiating a dopamine agonist in a low dose and a slow increase of dose may minimize gastrointestinal complaints and orthostatic hypotension. In general, cabergoline should be initiated 0.25 mg once or twice a week and ingested with some food and just before bedtime. Nausea is more common during bromocriptine use. Initial bromocriptine dose is twice daily 1.25 mg. In general, lower doses are accompanied with less severe side effects. However, some patients seem to be completely intolerant to dopamine agonists. For women, intravaginal administration of bromocriptine is reported to decrease the incidence of nausea (32).
Less frequent side effects are Raynaud’s phenomenon, depression, alcohol intolerance, addictive behavior, and constipation.
Macroprolactinomas often infiltrated the base of the skull, when treated with dopamine agonist, CSF leakage as rhinorrhea may occur in case of a rapid tumor shrinkage (33). Early recognition of this complication is important due to a potential risk of meningitis. Withdrawal or tempering of the dopa-mine agonist dose is necessary when CSF leakage occurs and, if necessary or persistent, neurosurgical intervention.
Valvular Heart Disease
Ergot derivatives, such as cabergoline and pergolide, when given in high doses are associated with valvular heart disease in, for example, Parkinson’s patients (27). This association appears to depend on dose and time of exposure. In Parkinson’s disease, however, doses greatly exceed dose regimens as used in endocrine diseases.
Initial reports on cardiac valvulopathy in Parkinson’s patients during cabergoline use triggered a number of studies assessing valvulopathy with cardiac ultrasonography in patients using cabergoline for hyperprolactinemia (34). Only one single study observed a higher frequency of moderate tricuspid regurgitation than age- and gender-matched subjects. None of the other studies observed any valvular regurgitation during long-term cabergoline treatment (34). Prolactinoma patients in these studies used standard doses of cabergoline of 0.5 to 1.5 mg/weekly. When prolactinoma patients use higher doses over longer time, a potential increased risk of developing valvular disease might exist although this has not been reported to date.
Nowadays, it is advised that cardiac ultrasonography should be performed approximately every 2 years in patients that use cabergoline >2 mg weekly. Also, dose adaptation to the lowest dose of cabergoline that is necessary to lower prolactin to the normal range is desirable (23).
Pregnancy
Initiation of a dopamine agonist can lead to rapid recovery of fertility even before menses is completely restored. Therefore, female patients of fertile age should be aware that initiation of dopamine agonist treatment could result in a pregnancy after only a few doses. The use of dopamine agonists during pregnancy is generally not recommended (13). In a selected group of macroprolactinomas, continuation of dopamine agonists may be prudent. Tumor behavior, invasiveness of the adenoma, and the relationship to vital structures, such as the optic chiasm, all influence the decision to continue dopaminergic treatment or not. Some reports do suggest that macroprolactinomas may grow or re-expand during pregnancy after discontinuation of dopamine agonists (13). Lactotroph hyperplasia of the normal pituitary gland may displace the prolactinoma, and high estrogen may stimulate tumor growth. In general, however, microprolactinomas as well as macroprolactinomas within the sellar bounderies seldom cause symptomatic tumor growth (13). Bromocriptine is the drug of choice during pregnancy. In more than 6000 pregnancies, no harmful effects were observed. Cabergoline seems to be safe as well; however, the number of reported pregnancies is low. Quinagoline has by far the lowest number of reported pregnancy outcomes and a poor safety profile and is therefore not recommended (13).
Level of Evidence of Statementsa
|
Statement |
Level of Evidence |
|
Dynamic testing to evaluate hyperprolactinemia should not be applied. |
1b |
|
A single prolactin assessment for the diagnosis of hyperprolactinemia is enough. |
1b |
|
Other causes of hyperprolactinemia should be excluded. |
1a |
|
Asymptomatic hyperprolactinemia does not need any treatment. |
4 |
|
Microprolactinoma that only have irregular menses can be treated with oral contraceptives or cabergoline. |
4 |
|
Cessation or switch of medication causes hyperprolactinemia.b |
2b |
|
Symptomatic micro- and macroadenomas should be treated with dopamine agonist. |
1c |
|
Cabergoline is the drug of choice because it has the highest efficacy in normalizing prolactin and tumor shrinkage. |
1c |
|
Women with prolactinomas need to discontinue dopamine agonist as soon as they know that they are pregnant. |
3b |
|
During pregnancy, prolactin assessment in prolactinoma patients is redundant. |
1b |
|
If dopamine agonists are indicated during pregnancy, bromocriptine is the drug of choice. |
3a |
a Summary of Endocrine Society Clinical Practice Guideline (13).
b Antipsychotic drugs should not be discontinued or switched without consent of the treating psychiatrist.
Grade of Strength for Recommendations
|
Recommendation |
Grade Strength |
|
Macro-prolactin assessment is not useful in symptomatic individuals. |
A |
|
Usually, a single prolactin assessment will diagnose hyperprolactinemia. |
A |
|
Other causes of hyperprolactinemia should be excluded when a hyperprolactinemia diagnosis is established. |
A |
|
Symptomatic micro- or macroprolactinoma should be treated with adopamine agonist. |
A |
|
Asymptomatic microprolactinoma do not need treatment. |
C |
|
In collaboration with an endocrinologist; formal visual field assessment followed by MRI without gadolinium in pregnant women with prolactinomas that experience severe headaches with or without visual field changes. |
B |
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Notes
* SN received research grants and speakers fees from Ipsen and Pfizer.
† AvdL consultant and received speakers fees from Novartis, Ipsen, and Pfizer.
