Approach

The primary goal of treatment is to suppress and normalize prolactin levels, thus restoring ovulation in women and normalizing testosterone and sexual function in men.

In addition, patients with macroprolactinomas are treated to achieve tumor size reduction and decrease mass effects, particularly visual defects. Intolerable galactorrhea also requires active treatment.

Women with microprolactinomas, mild galactorrhea, and normal menstrual cycles may be monitored and not treated.

Treatment with dopamine agonists

Medical treatment with dopamine agonists is the primary treatment in men and women for both microprolactinomas and macroprolactinomas.[11][16] Dopamine agonists are potent inhibitors of prolactin secretion and synthesis. These agents reduce the volume of the lactotroph cells, thus decreasing the size of both micro- and macroprolactinomas. This continuous treatment will normalize prolactin in about 90% of patients; restore gonadal function, libido, and fertility; and shrink the tumor.[11] Galactorrhea should disappear.

Cabergoline is the recommended first-line dopamine agonist due to superior efficacy in normalizing serum prolactin and reducing tumor size, better tolerability, and a more convenient dosing regimen.[11][16] Treatment usually starts at low doses to avoid adverse effects, with a gradual dose escalation during the first months upon achieving control of the hyperprolactinemia and tumor shrinkage. After these are achieved, and prolactin is stably controlled for 1-2 years, the dopamine agonist dose can be gradually decreased, provided it maintains normal prolactin levels and controls tumor size.

Women with microprolactinomas and amenorrhea or menstrual irregularities, who do not desire pregnancy, may be offered estrogen/progesterone treatment instead of a dopamine agonist.[11] Besides providing contraception, this treatment will achieve menstrual regularity. Oral estrogen/progesterone treatment does not appear to promote growth of microprolactinomas.[11]

Because the dopamine agonists bromocriptine and cabergoline decrease prolactin levels and promote the return of a regular menstrual cycle and ovulation, pregnancy may occur whilst women are taking these medications. They are usually discontinued as soon as pregnancy is confirmed.[11] In those patients with large macroprolactinomas, particularly those abutting the optic chiasm, dopamine agonists may be continued throughout pregnancy.[17][18] Due to its more widespread use, women are more likely to be receiving cabergoline rather than bromocriptine for treatment of their prolactinoma at the time of conception. Cabergoline has been introduced more recently than bromocriptine, and therefore, there are fewer safety data relating to maternal and fetal exposure to cabergoline compared with bromocriptine. Nevertheless, observational research has been unable to find an increase in miscarriage or fetal malformations in association with exposure to cabergoline in early pregnancy.[19] Bromocriptine is an alternative dopamine agonist that can be used for this indication.

Postmenopausal women with microadenoma or undetectable pituitary mass do not usually require any treatment. Galactorrhea usually improves when endogenous estrogen decreases postmenopausally.[Figure caption and citation for the preceding image starts]: Gadolinium-enhanced magnetic resonance imaging (coronal view) showing a 40 mm pituitary macroprolactinoma in a 41-year-old man before (A) and after (B) 2-month treatment with cabergolineFrom the collection of Dr Ilan Shimon [Citation ends].com.bmj.content.model.Caption@5bf3a736[Figure caption and citation for the preceding image starts]: Gadolinium-enhanced magnetic resonance imaging (sagittal view) showing a 40 mm pituitary macroprolactinoma in a 41-year-old man before (A) and after (B) 2-month treatment with cabergolineFrom the collection of Dr Ilan Shimon [Citation ends].com.bmj.content.model.Caption@3bc53dba

Dopamine agonist resistance and intolerance

Patients in whom prolactin does not normalize on maximally tolerated doses of dopamine agonists, or tumor size is not reduced by 50%, are considered to be dopamine agonist resistant.[16] Resistance to cabergoline occurs in approximately 10% of patients with a microprolactinoma compared with 15% to 20% with a macroprolactinoma.[20]

Patients resistant or intolerant to dopamine agonists should be referred for transsphenoidal surgery, in centers with experienced neurosurgeons, for prolactinoma resection.[11][21] Surgery will immediately improve visual function in most cases of macroprolactinomas compressing the optic tract. Transsphenoidal surgery may be complicated, particularly in cases of large and invasive macroadenomas, and can result in anterior pituitary dysfunction and/or diabetes insipidus requiring permanent hormonal replacement.

Malignant prolactinomas exhibiting metastatic spread within or outside the central nervous system are rare. Radiation therapy is rarely used and is reserved for dopamine agonist-resistant or malignant prolactinomas.[11]

Dopamine agonists and valvular heart disease

Reported associations between high doses of cabergoline used in the treatment of Parkinson disease and cardiac valvulopathy has led to concerns about the safety of cabergoline treatment in patients with prolactinomas.[22] However, patients receiving cabergoline for hyperprolactinemia are typically younger, female, and taking much lower doses than those used in Parkinson disease. Evidence does not support a clinically significant association between cabergoline treatment for prolactinomas and valvular heart disease.[23] Recommendations on the timing and frequency of screening for cardiac valve disease in patients receiving cabergoline for hyperprolactinemia vary.[24][25] Patients should receive the lowest effective dose of cabergoline for the shortest possible duration. Echocardiographic surveillance may be performed on patients likely to receive moderate or high doses of cabergoline for a considerable duration.[25][26]

Dopamine agonists and psychiatric adverse effects

Although dopamine agonists are well tolerated by the majority of patients for prolactinoma management, a small number of patients may develop psychiatric disturbances, including impulse control disorders.[17] Further studies are needed to elucidate specific risk factors for the development of psychiatric disturbance with dopamine agonists, but currently, clinicians are advised to monitor carefully for mood disturbance and the development of impulse control disorders. For those patients with pre-existing psychiatric disorders, dopamine agonists should be used with caution in the management of prolactinoma, and alternative treatment options, such as transsphenoidal surgery, should be considered.

Dopamine agonist withdrawal

In view of concerns about the association of the long-term use of dopamine agonists with valvular heart disease, there has been emphasis on a trial of drug withdrawal in certain patients with prolactinoma to minimize exposure.[27] A trial of dopamine agonist withdrawal is most likely to be successful if attempted in patients in whom there has been restoration of normal serum prolactin, significant reduction in tumor size on magnetic resonance imaging, low maintenance doses of dopamine agonists, and a treatment duration of at least 2 years.[11][28] Remission of hyperprolactinemia in patients with prolactinoma following dopamine agonist withdrawal varies between studies, with greater success in microprolactinomas (approximately 40%) compared to macroprolactinomas (approximately 30%).[28] Because approximately one third of patients may develop secondary hypogonadism following recurrence of hyperprolactinemia, regular monitoring of serum prolactin for the first year after drug withdrawal is recommended, with pituitary magnetic resonance imaging if hyperprolactinemia recurs.[11]

Use of this content is subject to our disclaimer