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
