Introduction

Hyperprolactinemia is the most common pituitary abnormality seen in women. It is the term simply given to having an elevated serum prolactin. Prolactin is made and stored from lactotroph cells in the pituitary gland. The control of prolactin is mainly inhibitory, with a few stimulating factors. Thyroid-releasing hormone (TRH) directly stimulates prolactin release. Estrogen can increase prolactin levels as well by augmenting TRH. The pituitary is inhibited by the neurotransmitter dopamine. Dopamine primarily controls release. Serotonin has been hypothesized to increase prolactin, but this has not been substantiated.[1] Prolactin can also come from decidualized stroma; such is not regulated by the pituitary.

The principal function of prolactin is to stimulate growth of mammary tissue, and subsequently to produce and secrete milk. Its secretion fluctuates over the course of the day, and is highest during sleep and lowest while awake. This is thought to be related to a person’s circadian rhythm.[3] For this reason the most common timeframe for checking prolactin levels is first thing in the morning. In women, levels additionally fluctuate throughout the menstrual cycle with the peak in mid-cycle.

The prevalence and incidence of hyperprolactinemia varies depending on the population. In the general population, the prevalence of prolactinomas ranges from 6% to 50%.[4, 5] The prevalence of hyperprolactinemia has been reported at 90 per 100,000 in women with the peak age at 25–34 years old.[6] When special populations are defined the incidence is higher. Hyperprolactinemia can occur in 15.7% of women seeing an infertility specialist.[7] In women with a combination of oligomenorrhea or amenorrhea with galactorrhea, 75%–84% had hyperprolactinemia.[8] Specifically, in adolescents and young women with oligomenorrhea or amenorrhea, up to 13.8% were noted to have hyperprolactinemia, but in all women presenting with amenorrhea 30% may have prolactinemia.[9] For women who have abnormal uterine bleeding in the third decade of life, 9.4% have hyperprolactinemia.[10] Hyperprolactinemia can occur in men, but some estimate up to 10 times more women have this condition prior to menopause then men over a lifetime. After menopause the incidence of hyperprolactinemia is equal between men and women.

Clinical presentation

Multiple clinical symptoms and physical signs are related to hyperprolactinemia. Resulting decreases in the secretion of gonadotropin-releasing hormone and the subsequent effects on other stimulating sex hormones cause many of the clinical symptoms. Hyperprolactinemia not only suppresses release of lutenizing hormone, but has direct effects on the ovary, thereby affecting both estrogen and progesterone production.[11] Galactorrhea, amenorrhea, and infertility are the three most common presenting complaints. The symptoms otherwise vary depending on the age of the woman and the size of any adenoma. Infertility can occur even with normal menstrual cycles. Hyperprolactinemia may lead to shortened luteal phase and insufficient progesterone. If the hyperprolactinemia coexists with polycystic ovarian syndrome, there can be a delay in diagnosis unless the patient has galactorrhea. In adolescents there can be a delay in puberty.[12] Additionally subtle psychologic symptoms have been noted to occur with hyperprolactinemia.[13] In women of all ages decreased libido may occur.

Large adenomas can cause mass effects such as visual changes and headaches. The visual symptoms are variable and can include classic bi-temporal hemianopsia to small partial defects to scotomatas.[14] In addition 10% of tumors may invade the cavernous sinus with subsequent cranial nerve palsies.[15] Postmenopausal women tend to present later in the course as the typical menstrual abnormalities are not symptoms; they tend to present with visual symptoms, headaches, or late galactorrhea with larger prolactinomas. In a study of fourteen women in three countries diagnosed from age 54 to 75, thirteen of the fourteen had macroprolactinomas, with eight of them having suprasellar extension. The mean prolactin level was 1,783 and significantly higher than in premenopausal women.[16] It seems that women have a higher risk of macroprolactinomas as they get older.[17] They can also have sexual dysfunction. These symptom are similar to the ones seen when men present with hyperprolactinemia.

Newer data confirms that hyperprolactinemia increases risk for osteoporosis and fractures. In a study of 78 women aged 20–81, 33.3% had osteopenia and 23.1% had osteoporosis. This was significantly higher than the control subjects. In the same study the vertebral fracture rate was higher in women with hyperprolactinemia and independently associated with the duration of the disease.[18] Another study looking at women with forearm and spine fractures found the effect on the bone greater in the spine which had a 25% decrease in density compared with controls. Unfortunately, even after treatment for the hyperprolactinemia, bone density was not restored.[19] At this time, hyperprolactinemia is not part of the workup for pathologic fractures, but could be a presenting sign especially in the postmenopausal woman.

Causes of hyperprolactinemia

Some normal physiologic causes of hyperprolactinemia exist such as pregnancy, lactation, exercise, or periods of stress. Nipple stimulation outside of pregnancy and breastfeeding does not cause hyperprolactinemia.[20] Transient hyperprolactinemia has been associated with both generalized and partial seizures.[21] This transient hyperprolactinemia after a seizure resolves within an hour. Medication induced hyperprolactinemia is found with many antipsychotics, antidepressants, estrogen, opiods, and some antihypertensives and gastrointestinal drugs (see Table 30-1). Primary hypothyroidism may cause hyperprolactinemia due to stimulation of TRH. Chronic renal failure can also cause hyperprolactinemia secondary to impaired renal degradation. Infiltrative disorders of the pituitary such as sarcoidosis increase prolactin levels. Chest wall injuries can induce hyperprolactinemia as well. The single most common cause of hyperprolactinemia is a prolactin adenoma accounting for 60% in some studies.[1, 12] See Table 30-2 for a complete list of causes.

Other associated disorders are seen with hyperprolactinemia. It can coexist with polycystic ovarian syndrome;[22] there is significant overlap in symptoms between these conditions, making it challenging to discern if one causes the other or they merely coexist frequently. Many rheumatologic disorders can coexist with hyperprolactinemia including systemic lupus erythematosus, rheumatoid arthritis, and systemic sclerosis. Cranial abnormalities associated with hyperprolactinemia include empty sella syndrome, many infiltrative diseases, radiation to the pituitary area, and trauma.[1, 12] Prolactinomas have also been associated with multiple endocrine neoplasia type I.[23]

Natural history

Microprolactinomas have not been shown to have significant growth over time with the longest study having an eight-year follow-up. Note that in these studies, newer imaging such as advanced computed tomography (CT) was not available and magnetic resonance imaging (MRI) capability was rare.[24] In a study of 38 untreated patients over 31 months of follow-up, there was no significant changes in tumor size.[25] In a retrospective study of 70 patients with hyperprolactinemia, excluding macroadenomas, three out of ten normalized prolactin with no treatment over time. In those women with a pregnancy, 35% normalized requiring no further treatment versus 14% who did not have a pregnancy (P <0.05).[26] In women there is a 45% chance of normalization of prolactin levels after menopause.[27] Therefore, it seems that a percentage of women with idiopathic hyperprolactinemia and those with microadenomas have the potential for spontaneous resolution over time. There are no specific studies following the long-term natural history of macroprolactinomas.

Recent improved imaging shows many prolactinomas have had hemorrhage. In a study of 368 patients, the overall prevalence of hemorrhage was 6.8%. However, there was a significant difference in the rate of hemorrhage between macroadenomas and microadenomas at 20.3% and 3.1%, respectively. In this study, 87% of patients with hemorrhage resolved over time with dopamine agonist treatment.[28]

Diagnostic workup

Laboratory testing is the key to the initial diagnosis of hyperprolactinoma. Any woman with the combination of galactorrhea and amenorrhea or oligomenorrhea should be tested for hyperprolactinemia. Normal ranges vary slightly by lab but tend to be <25 mcg/L in women. There is a phenomenon known as the “hook effect” when the prolactin clumps and causes a falsely lower prolactin level compared with the adenoma size seen in imaging. Current guidelines recommend a single serum measurement of prolactin for diagnosis. There is a recommendation against dynamic testing of prolactin. In general the level of prolactin matches the size of the adenoma. This is not precise, but it is accepted that levels greater than 500 mcg/L are diagnostic of a macroadenoma.[2]

After the initial elevated lab test, causes of hyperprolactinemia that could be reversible must be excluded. This would include checking TRH, checking for renal abnormalities, and a thorough medication review. There is some evidence to support serum testing for the larger prolactin molecules. This is not clearly defined. If hyperprolactinoma is felt to be drug induced, removal of the offending agent should occur for three days with repeat prolactin serum testing. Current consensus is to avoid treating asymptomatic drug-induced hyperprolactinemia.[2] Additional testing of the pituitary as a whole is recommended by some, and may be warranted when the prolactin is very high or other symptoms are present.

Radiographic features of prolactinomas are best seen on gadolinium enhanced MRI; this is considered the imaging of choice. Patients with visual symptoms or severe headaches may receive urgent CT first. If this is done, an MRI should be performed to complete the imaging workup. In one recent guideline, however, specific radiologic testing of all patients with hyperprolactinemia was not mentioned.[2]

At the time of initial diagnosis, patients may be divided into subsets based on the size of the prolactinoma. Microadenomas are defined as prolactinomas less than 1 cm in size, and macroadenomas are greater than 1 cm. Giant prolactinomas are a special higher risk subset of prolactinomas. These adenomas are larger than 4 cm and/or demonstrate more than 2 cm of suprasellar extension. These tumors tend to cause more visual symptoms.

Treatment and follow-up

The treatment of hyperprolactinemia in women varies based on the etiology, the patient’s desire to conceive, symptoms present, and the size or expansion of any adenoma. If the hyperprolactinemia is drug induced, the offending agent should be discontinued. If for some reason the drug cannot be stopped, a dopamine agonist may be started to treat symptoms. Current recommendations state that a patient with asymptomatic drug-induced hyperprolactinemia does not require treatment.[2]

Women with hyperprolactinemia who do not want to conceive and have no neurologic symptoms can choose to have no treatment. Additionally, the presence of a microadenoma does not require treatment unless symptoms are present.[2] If no treatment is started, periodic prolactin levels should be performed; the consensus periodicity is annual. If at any time the patient develops symptoms, treatment with a dopamine agonist is started. If a microadenoma enlarges (even without symptoms), treatment should be started.

Any woman who desires pregnancy or has a macroadenoma at the time of diagnosis should be treated with a dopamine receptor agonist. Both bromocriptine and cabergoline are available for use. Pergolide is an older drug and no longer available. Quinagolide is used in Europe but is not available in the United States.

Bromocriptine is an ergot derivative developed and approved in 1967 for the treatment of hyperprolactinemia. It is the best studied option in all age groups and during pregnancy. It has a half-life of 7–14 hours thus requiring twice daily dosing. The typical starting dose is 2.3 mg per day in divided dose and increased to a maximum of 15 mg per day. The incidence of adverse effects is 69%, with nausea, headaches, and dizziness being the most common. Many patients discontinue use secondary to the side effects. Side effects are more common when the drug is initiated and increased. Titrating slowly may therefore be effective.[29] Another potential side effects is postural hypotension.[30] Two rare adverse effects are pain in the digits related to vasospasm that occurs in response to cold,[31] and precipitation of psychotic episodes.[32] Nonsurgical cerebrospinal fluid (CSF) rhinorrhea is sometimes seen as the medication shrinks the tumor; this often resolves spontaneously.[29]

Bromocriptine is an effective medication to treat hyperprolactinemia. Early trials in the 1980s demonstrated normalization of prolactin, decreased tumor size, and visual field improvements.[33] Bromocriptine has had studies with the longest follow-up reaching 10 years. A recent meta-analysis of 39 trials further defined the effectiveness of bromocriptine. Combining the data, there was a median of 68% of patients having normalization of prolactin, and 62% having tumor shrinkage. Clinical symptoms including galactorrhea, amenorrhea, infertility, and visual field defects improved by 85%, 78%, 67%, and 53%, respectively.[34]

Cabergoline is a longer acting dopamine agonist used to treat hyperprolactinemia. Its long half-life of 65 hours allows for twice weekly or even weekly dosing. The starting dose is 0.25 mg twice weekly. The standard schedule includes an increase every four weeks. The standard dose ranges from 0.5 mg to 2.0 mg per week. Compared with bromocriptine, there are fewer total side effects. The most common side effects are nausea, headache, and dizziness. Databases report 2% of patients will discontinue the drug due to side effects. The once weekly dosing can improve patient compliance.[35] In a study of 162 patients, 85% had normalization of prolactin levels, and more than 90% of both amenorrheic and oligomenorrheic women resumed normal menstrual cycles. Only 3% of these patients discontinued use due to side effects.[36]

Cabergoline has recently been viewed as the drug of choice. It is more effective in normalizing prolactin, shrinking adenomas, and avoiding secondary procedures compared to bromocriptine.[2] One study compared the extent of tumor size reduction and prolactin level normalization among 110 patients with macroprolactinomas. Of these 110 patients, 26 were drug naïve, 19 were intolerant of other dopamine agonists, 47 were resistant to other dopamine agonists, and 28 were responsive to other dopamine agonists but no longer using them due to poor compliance or drug unavailability. The prolactin normalization in the 19 patients intolerant of other agonists was 94.7%. The prevalence of macroprolactinoma shrinkage was greatest among drug-naïve subjects at 92.3%. However, significant tumor shrinkage (>50%) still occurred in the intolerant and resistant groups, with a rate of 42.1% and 30.3%, respectively. Importantly this study demonstrated that patients who were intolerant or resistant to other dopamine agonist may respond to cabergoline when the dose was increased to 3 mg–3.5 mg weekly.[37] In another study of macroprolactinomas and resistance, 122 patients were enrolled; 72 of them were women. Normalization of prolactin levels occurred on 83% with doses of cabergoline less than 1.5 mg per week. Patients were considered partially resistant if higher doses were used. By increasing the dose to 3.5 mg per week, 94% of patients had normalization. Those patients who required a higher dose were more likely to be men or have cavernous sinus invasion.[38] Further evidence for the use of cabergoline at high doses was conducted in single-arm prospective study of 150 patients, consisting of both men and women. These patients included those resistant or intolerant to other dopamine agonists. Prolactin levels were normalized in 99.3% (149) of patients within one year using an individualized treatment protocol with higher doses of cabergoline up to 5 mg per week. There were no dropouts due to side effects.[39] These studies are the evidence behind the current recommendations that if bromocriptine does not work, a switch to cabergoline should be made. Furthermore, if standard dosing does not seem to induce normal prolactin levels, higher doses of cabergoline should be used.[2]

When bromocriptine and cabergoline have been studied together, cabergoline has demonstrated superior results with fewer side effects. In a multicenter, prospective randomized comparative trial conducted in 459 hyperprolactinemic women (279 microadenomas, 3 macroadenomas, 167 idiopathic hyperprolactinemia, 10 other), of those women treated with cabergoline, 83% achieved normoprolactinemia, 72% resumed ovulatory cycles, and 3% discontinued the medication because of adverse effects. Of the women treated with bromocriptine, 59% achieved normoprolactinemia, 52% resumed ovulatory cycles, and 12% stopped the drug because of adverse effects.[40] Additionally in a meta-analysis including six observational studies and three randomized trials, cabergoline was more effective than bromocriptine. Specifically bromocriptine was less effective in reducing persistent hyperprolactinemia, galatorrhea, and amenorrhea.[34] A more recent meta-analysis confirmed these results.[41] These studies confirmed that cabergoline is the drug of choice for hyperprolactinemia.

Cabergoline appears to have increased effectiveness, but concerns exist regarding valvular heart disease. A large amount of data shows increased prevalence of valvular heart disease in Parkinson’s patients using dopamine agonists.[42] The most recent review pooled data from multiple observational studies showed significant increased risk (RR = 6.38 [3.17–12.81]) of developing moderate to severe aortic regurgitation.[43] Doses of dopamine agonists in Parkinson’s are higher than those used in hyperprolactinemia. The evidence for valvular disease in patients being treated for hyperprolactinemia has been conflicted until recently.[44–47] Recent agreement is that there is no significant risk of valvular heart disease with routine dosages for hyperprolactinemia.[48–50] Further study is needed concerning the higher doses of cabergoline used in resistant adenomas.

A small group of patients will be resistant to treatment with dopamine agonists. Approximately 80% of this group who do not respond to treatment with bromocriptine will respond to cabergoline.[51] Complete resistance to cabergoline is extraordinarily uncommon, and most “partial” resistance can often be overcome by increasing the dose. One study of 150 patients found that all but one patient could get normalization of prolactin with increased doses of cabergoline.[39]

A small subset of patients can discontinue the medication once the tumor shrinks and/or normal prolactin levels are achieved. The exact reason this occurs is unclear. In a study of 89 patients who were treated with either bromocriptine of cabergoline for several years and then after withdrew from treatment, 36% remained in remission beyond one year.[52] In that study, there was no difference between the two medications. Other studies demonstrated rates of recurrence at one year from 36% to 60%.[53–55] After review of these studies, it is reasonable to give patients a trial of dopamine agonists after several years of prolactin normalization and tumor shrinkage. Since the return to hyperprolactinemia may occur as early as three months after medication termination, periodic prolactin levels should be considered. No consensus exists for the frequency of prolactin levels follow-up.

There are very few studies defining the optimal management of giant prolactinomas. Often a combination of treatment is used with cabergoline being the medication of choice.[56] A series of 68 patients with invasive prolactinomas were managed with a combination of treatments, with 33 having medical treatment with bromocriptine initially and the other 35 with surgical treatment first. Many required adjunct treatment after the initial treatment for complete management.[57] Another series of patients with parasellar extension demonstrated this feature of a macroprolactinoma may predict resistance to dopamine agonist therapy.[58]

Surgery is typically reserved for those with one of the following issues: rapid visual loss, failure of medical therapy to normalize prolactin levels and improve symptoms of hypogonadism, failure of medical therapy to slow tumor growth, tumor expansion during pregnancy not controlled with medication, and preconceptionally in a woman with problems during a prior pregnancy. Surgical options have specific risks and benefits. Transphenoidal surgical approaches are most common and have demonstrated remission rates up to 90%.[59, 60] In a recent series of 138 women under the age of 40, initial cure rate for macroadenomas was 95%. Over time there were some recurrences for a final longer-term cure for macroadenomas of 89%. Macroadenomas without invasion were more likely to have a cure.[61] The surgical approach is individualized because there are no randomized controlled trials of the surgical approach. Mortality following surgery is reported as 1%. Pituitary failure and diabetes insipidus occur in up to 20% of patients. More uncommon complications include infection, CSF leaks, visual loss, and hypothalamic injuries.[62] Endoscopic procedures and intraoperative MRI are gaining recognition but are in early stages of development. Fractionated guided radiotherapy and Gamma Knife stereotactic radiosurgery have been reserved for recalcitrant cases. Most studies include all pituitary tumors. In one study of 33 tumors (8 prolactinomas), morbidity included visual field defects and hypopituitarism.[63]