Prolactinomas, benign lesions that produce the hormone prolactin, are the most common hormone-secreting pituitary tumors.[1] Causing hyperprolactinemia, prolactinomas can reduce estrogen levels in women and testosterone concentrations in men and may result in infertility. Based on its size, a prolactinoma can be classified as a microprolactinoma (< 10 mm diameter) or a macroprolactinoma (>10 mm diameter). The tumor can be assessed through hormone testing and magnetic resonance imaging (MRI) or computed tomography (CT) scanning. Bromocriptine (BEC) is generally considered to be the agent of choice in the treatment of prolactinoma. Surgically, transsphenoidal pituitary adenomectomy is the preferred treatment in patients with microprolactinoma and in most patients with macroprolactinoma.[2]
Signs and symptoms of these pituitary tumors include the following:
Additional complications include cranial nerve palsies, hydrocephalus, and apoplexy (from hemorrhage/infarction into the tumor).[7]
Laboratory studies include the following:
After performing biochemical testing, order a magnetic resonance imaging (MRI) scan of the pituitary hypothalamic area (with gadolinium enhancement) or a computed tomography (CT) scan of the region (with contrast) to determine if a mass lesion is present.
Treatment is indicated if mass effects from the pituitary tumor and/or significant effects from hyperprolactinemia are present.[8] Bromocriptine (BEC) is generally considered to be the agent of choice in the treatment of prolactinoma because of its long track record and safety. As a dopamine (DA) agonist, it decreases the synthesis and secretion of PRL.[9] It also decreases the rate of tumor cell division and the growth of individual cells.
Other medical treatments for prolactinomas are available for patients who do not respond to BEC or for those who cannot tolerate the drug. Cabergoline, an ergot derivative, is a long-acting DA agonist and is available in the United States.
In those patients with DA agonist–resistant prolactinomas (DARPs) having persistent hyperprolactinemia despite surgical debulking, with or without radiotherapy, temozolomide, a chemotherapeutic alkylating agent, has been recommended.[10]
Transsphenoidal pituitary adenomectomy is the preferred surgical treatment in patients with microprolactinoma and in most patients with macroprolactinoma.[2] A combination of surgery followed by postoperative medical treatment with BEC or one of the other agents is used in patients with incomplete resolution of elevated PRL levels and in persons with residual tumors seen on follow-up imaging studies.
Tumor formation is due to neoplastic transformation of anterior pituitary lactotrophs, resulting in excess synthesis and secretion of prolactin (PRL). Linkage to aryl hydrocarbon-interacting protein gene (AIP) mutation has been identified in some families with prolactinoma and in childhood-onset pituitary adenomas.[11]
Physiologically, PRL, a polypeptide hormone consisting of 199 amino acids, is regulated by hypothalamic factors. These include prolactin-releasing factors (PRFs) and prolactin-inhibitory factors (PIFs).
Dopamine (DA) is the principal PIF, and thyrotropin-releasing hormone (TRH), vasoactive intestinal peptide, and peptide histidine methionine are the putative PRFs. The physiologic role of these PRFs is not established. A delicate balance between the PRFs and PIFs normally keeps the serum PRL level within a physiologic range. Moreover, the interplay of various neurohormonal factors results in a pulsatile secretion of PRL from the pituitary gland. Prolactinoma is one of the several causes of pathologic hyperprolactinemia.[8, 12, 13, 4, 14]
A retrospective study by Peng et al of 102 patients found that growth hormone deficiency and hypogonadism were the most frequent types of pituitary hormone dysfunction in adult males with prolactinomas, with hypocortisolism occurring less often.[15] This observation should come as no surprise, since prolactinomas in men are often larger (macroprolactinomas) and are thus likely to cause tissue compression, in contrast to prolactinomas in women, which are often small (microprolactinomas) at the time of initial diagnosis.
United States
The exact frequency with which prolactinomas occur in the general population is not clearly established. In nonselected surgical series, this tumor accounts for approximately 25-30% of all pituitary adenomas. Some growth hormone (GH) – producing tumors also cosecrete PRL. Microprolactinomas are much more common than macroprolactinomas.
International
In a study of 81,449 inhabitants of Banbury, Oxfordshire, in the United Kingdom, Fernandez et al determined the incidence of pituitary adenomas there to be 77.6 cases per 100,000 population, with the majority of cases (57%, or 44.4 persons per 100,000 population) being prolactinomas.[16] It was also determined that prolactinomas accounted for most pituitary adenomas in persons up to age 60 years, the incidence being 75% of pituitary adenomas occurring in persons up to age 20 years, and 61% of pituitary adenomas in persons between the ages of 20 and 60 years. Moreover, prolactinomas accounted for 76% of pituitary adenomas in females, although in males, the majority of pituitary adenomas (57%) were nonfunctioning lesions.
The incidences of nonprolactinoma pituitary adenomas were as follows: nonfunctioning pituitary adenomas, 28%; adenomas associated with acromegaly, 11%; corticotroph adenomas, 2%; and adenomas of unknown functional status, 2%.
Among patients with prolactinomas, as many as 60% of the males present with macroprolactinomas, while 90% of the females present with microprolactinomas. This may partially be due to the fact that the male patients often present much later (for clinical evaluation of hypogonadism) than do the female patients (for clinical evaluation of amenorrhea).[5]
Patients with microprolactinoma generally have an excellent prognosis. In up to 95% of patients, these pituitary tumors do not enlarge over a 4- to 6-year follow-up period. These patients generally do well for extended periods on suppressive therapy with DA agonists.
Macroprolactinomas have a tendency to grow with time and require aggressive treatment to prevent complications. The growth rate varies with the individual and cannot be reliably predicted. Careful monitoring of clinical signs and symptoms, coupled with pituitary gland imaging and with serial measurements of serum PRL levels (ie, to detect any major change in tumor behavior), remain the cornerstones of follow-up for these patients.[17] .
A study by Sala et al indicated that in patients with prolactinomas undergoing cabergoline treatment, the prolactinoma recurrence rate does not decline even if therapy is continued for over 3 years prior to withdrawal. In the study, 74 patients with a prolactinoma were separated into three groups, including those treated with cabergoline for 3 years, those treated for 3-5 years, and those treated for more than 5 years. The prolactinoma recurrence rate within 12 months of treatment withdrawal did not significantly differ between the groups. Moreover, microadenomas and macroadenomas showed a similar recurrence risk, although patients with pituitary gland deficits at diagnosis had a higher rate of recurrence.[18] Most endocrinologists would recommend a drug holiday at 2 years of therapy to determine whether, after 3 months of observation, drug treatment needs to be continued. Patients requiring drug treatment at three years would obviously include a significant number of those who failed the drug holiday at 2 years. One would, therefore, not expect any difference in the recurrence rate at 3 years or after, as borne out in this study.
In contrast to the Sala study’s results, however, a report by Teixeira et al found evidence that macroprolactinomas have a higher relapse rate than do microprolactinomas following dopamine agonist withdrawal.[19]
A population-based, retrospective, open-cohort study by Toulis et al indicated that prolactinomas in males, but not females, increase their risk of incident cardiovascular disease (CVD). The investigators found that males in the study had an incident CVD rate of 14.8 per 1000 person-years, compared with 1.8 per 1000 person-years for females.[20]
The symptoms of prolactinoma should be explained to the patient, and patients should be advised to report any new or worsening symptom.
Female patients of reproductive age should be encouraged to practice barrier methods of contraception while on BEC (or similar agents), until menstrual cycles normalize. This facilitates accurate timing of any conception that may ensue and allows the physician to withhold BEC treatment upon conception.
For patient education information, visit eMedicineHealth's Women's Health Center and Pregnancy Center. Also, see eMedicineHealth's patient education articles Amenorrhea and Birth Control Types (Effectiveness and Side Effects).
Prolactinomas can cause symptoms secondary to the hormonal effects of excess PRL and to the space-occupying effects of the tumor itself.
The clinical features of sustained hyperprolactinemia (which vary with the duration and degree of the condition, as well as with the age and sex of the patient) are as follows[12, 14] :
Correlating with the size of the tumor, the space-occupying effects of prolactinoma are same as any other large tumor:
In women, focus the physical examination on assessment for galactorrhea and the identification of clinical signs of estrogen deficiency.
In men, examine testicular size and consistency, as well as the pattern of hair on the body. Also assess for the rare occurrence of gynecomastia.
In male and female patients, assess visual acuity and visual fields (by the confrontation method) and perform a cranial nerve examination at the bedside to help determine if the tumor has caused any mass effect.
Serum PRL
Measure serum PRL levels on 1 or more occasions, especially if the elevation is modest. Do not measure the PRL level directly after performing a breast examination, because the breast examination may cause a physiological PRL elevation.
Serum pregnancy test
Always consider the possibility of pregnancy in reproductive-aged females, because this is the most common cause of secondary amenorrhea in this group.
Serum TSH
Measure TSH levels to exclude the possibility of an elevated PRL level occurring secondary to an elevated TRH level. TRH is one of the PRFs. If the TSH level is elevated, confirm the finding by measuring the free thyroxine level.[23]
In a male presenting with symptoms of hypogonadism, measure serum testosterone or bioavailable testosterone levels.
In a patient with a history suggestive of adrenal insufficiency, measure basal and cosyntropin-stimulated cortisol levels.
In a person with features consistent with acromegaly, measure serum insulinlike growth factor-1 levels.
Exclude other possible systemic causes for hyperprolactinemia, such as chronic renal failure or cirrhosis, using appropriate laboratory tests as warranted.
After performing biochemical testing, order a magnetic resonance imaging (MRI) scan of the pituitary hypothalamic area (with gadolinium enhancement) or a computed tomography (CT) scan of the region (with contrast) to determine if a mass lesion is present.
MRI is better for soft-tissue delineation and for the identification of a small lesion. CT scanning is better for the identification of any bone distortion or destruction. Special attention is given to the size of the tumor and its encroachment on surrounding structures (eg, the optic chiasm, other cranial nerves) and resulting effects (eg, bony destruction).
Good correlation exists between the size of the prolactinoma and the degree of elevation of the serum PRL. A serum PRL value of 200 ng/mL or greater in the presence of a macroadenoma (>10 mm) is virtually diagnostic of prolactinoma. However, if the serum PRL value is less than 200 ng/mL in the presence of a large pituitary mass lesion, this is more suggestive of hyperprolactinemia occurring secondary to stalk compression by the lesion; it could also indicate the occurrence of the hook effect, which is an artifact in the lab method used to measure prolactin.[24] Immunoassays used to measure PRL, such as immunoradiometric assay (IRMA), enzyme immunoassay (EIA), and immunochemiluminometric assay (ICMA), employ a "sandwich" (2-antibody) technique. When the PRL level is markedly elevated, the excess antigen (PRL) is washed off in the liquid phase of the sandwich assay and thereby results in gross underestimation of antigen levels in the specimen. When this is suspected, serial dilutions of theserumsamplewill reveal the actual hormone level.
Repeat scans are obtained postoperatively and during follow-up examinations thereafter, or they are obtained after medical treatment to help determine if the tumor has progressed or regressed. The frequency with which repeat imaging scans are performed is individualized to the patient. For instance, in patients with microprolactinoma, pituitary MRI could be performed 1 year after treatment start and then every few years thereafter, less frequently than such scanning would be performed in patients undergoing treatment for macroprolactinoma.
When the tumor is large and is in close vicinity of the optic chiasm, formal visual-field (VF) testing by an ophthalmologist is performed prior to any therapy. The same testing is repeated after treatment is begun, to monitor the patient's response to treatment.
If a pituitary/hypothalamic lesion other than a prolactinoma (such as lymphocytic hypophysitis or a granulomatous condition) is considered, biopsy of the lesion by a neurosurgeon may be indicated.
Treatment is indicated if mass effects from the tumor and/or significant effects from hyperprolactinemia are present.[8, 25]
Although the natural history of prolactinomas is unclear, most microprolactinomas (up to 95%) do not progress to macroadenomas, as determined after a 4- to 6-year observation period. Hence, if a patient with a microprolactinoma has minimal symptoms, the patient can be monitored closely with serial estimations of serum PRL levels combined with imaging studies at yearly intervals. However, if a patient with a microprolactinoma has significant effects from the hyperprolactinemia, treatment is indicated.
Any patient with macroprolactinoma needs treatment, because the tumor has already shown a propensity to grow. Such treatment includes the following:
Bromocriptine (BEC) is generally considered to be the agent of choice in the treatment of prolactinoma because of its long track record and safety. As a DA agonist, it decreases the synthesis and secretion of PRL.[9] It also decreases the rate of tumor cell division and the growth of individual cells.
Typically, BEC is administered at an initial dose of 1.25 mg nightly with food and is gradually increased to 2.5 mg bid in 1-2 weeks, as tolerated. Doses larger than 7.5 mg/d are seldom needed except in the treatment of macroadenomas.
Common adverse effects include nausea, nasal stuffiness, and dizziness associated with orthostatic hypotension. Others include vasospasm in the peripheral circulation and exacerbation or unmasking of depression and psychosis.
In patients who are intolerant to even small doses of BEC, one alternative is to administer the same daily dose intravaginally, a method that has almost equal efficacy.
Normalization of PRL levels occurs in 85-90% of all patients with prolactinomas.
In microprolactinomas, PRL levels return to normal within days to a few weeks of starting treatment in almost all patients who can tolerate appropriate doses of BEC. If PRL levels normalize, gonadal function also typically has a near-total recovery. Menses return to normal within a few months. Sometimes, pregnancy can occur before the resumption of menstruation; therefore, the couple must be advised to use barrier methods of contraception until normal menses have returned.
In macroprolactinomas, BEC treatment results in some reduction of tumor size in up to 80-85% of the patients. Significant VF improvements have been noted to occur in as few as 1-3 days, and significant changes on imaging findings occur as soon as 2 weeks after starting treatment.
In contrast to patients with microadenomas, resolution of hyperprolactinemia is often incomplete in patients with macroadenomas. However, the extent of reduction in tumor size is not well correlated with the changes in serum PRL levels. Nevertheless, reductions in PRL levels always precede tumor shrinkage, and patients who do not show a drop in PRL do not have any tumor shrinkage.
A reduction in tumor size is often accompanied by improvement in pituitary function. Examples include improved serum testosterone levels and an increased sperm count.
Once normalization of PRL levels is achieved and sustained, the dose of BEC is gradually tapered to approximately 2.5 mg/d. If PRL levels and tumor size are stable on the above dose, consider tapering BEC to the lowest dose possible. The patient should be evaluated periodically with monitoring of symptoms, PRL levels, and radiological changes.
A study by Wu et al indicated that DA agonists can provide long-term management of invasive giant prolactinomas. The study, which had a mean 135.5-month follow-up period, found that patients on BEC achieved long-term control of their disease with regard to tumor shrinkage and normalization of PRL level. However, the investigators also determined that in patients under age 25 years, there was a tendency toward persistent hyperprolactinemia even with long-term DA agonist therapy.[26]
Other medical treatments are available for prolactinoma patients who do not respond to BEC or for those who cannot tolerate the drug.
Cabergoline, an ergot derivative, is a long-acting DA agonist and is available in the United States. It is usually better tolerated than BEC, and its efficacy profiles are somewhat superior to those of BEC. It offers the convenience of twice-a-week administration, with a usual starting dose of 0.25 mg biweekly to a maximum dose of 1 mg biweekly. Some studies have shown efficacy even with once-a-week dosing. Cabergoline appears to be more effective in lowering prolactin levels and restoring ovulation. Up to 70% of patients who do not respond to BEC respond to cabergoline.[27] The only problem is cost. Side effects are somewhat fewer than with BEC and include headache, nausea, postural hypotension, and fatigue.[28]
Quinagolide is a nonergot DA agonist that has a long duration of action but is not yet available for use in the United States. It can be administered once daily. Efficacy and tolerance are comparable to that of BEC.
A study of patients with prolactinoma demonstrated that attempting DA agonist withdrawal in patients who have been treated for 2 years is practical and safe if normalization of prolactin levels and evidence of tumor reduction are observed.[29]
Pharmacologic resistance to DA agonists refers to a failure to respond to such agents in terms of a normalization of PRL levels and a reduction in the size of prolactinoma by at least 50%. DA agonist resistance results primarily from a reduction in D2 receptors on tumor cells.[30]
In some patients with prolactinoma who have adequately responded to medical treatment, withdrawing medical treatment after about 24 months may be possible. Although no clear predictive criteria for such successful withdrawal exist, evidence indicates that the recurrence of hyperprolactinemia is generally lower in patients with microadenomas than in those with macroadenomas. Hyperprolactinemia is more likely to recur in patients with tumor remnant on pituitary MRI than it is in patients with no such remnant. In very large adenomas, regrowth of tumor is often seen after the withdrawal of medical treatment. In any case, if medical treatment is withdrawn, close clinical, biochemical, and radiologic monitoring is warranted to look for evidence of tumor recurrence.
Most prolactinomas are medically responsive to dopamine agonist therapy. Slightly less than 10% of patients with prolactinomas do not respond to such treatment. Dopamine agonist resistance consists of failure to achieve normal prolactin level on maximally tolerated doses of dopamine agonist along with a failure to achieve a 50% reduction in tumor size.[31] These patients harbor tumors that are more likely to be invasive macroadenomas, more proliferative, more angiogenic, and more likely to exhibit cellular atypia. A few of these patients have malignant prolactinomas.[32]
In those patients with DARPs having persistent hyperprolactinemia despite surgical debulking, with or without radiotherapy, temozolomide, a chemotherapeutic alkylating agent, has been recommended.[10] Several case reports have shown temozolomide to reduce prolactin level and control tumor growth.[33, 34] Despite this, treatment of malignant prolactinomas is difficult, and survival is approximately one year.[35]
Radiation treatment (XRT) has had a less prominent role in the treatment of prolactinomas. Following conventional XRT, PRL levels normalize in only approximately 25% of patients. The major complication of this treatment is hypopituitarism, which occurs in 12.5-80% of patients. Other complications include optic nerve damage and neurologic dysfunction (see Complications).[36]
Because of the excellent results produced by medical treatment, with or without surgery, XRT is seldom used. XRT is considered only in select cases, ie, when there is rapid tumor regrowth despite medical and surgical treatment.
During pregnancy, a physiologic doubling occurs in the volume of a normal pituitary gland. Moreover, prolactin levels increase by 10-fold during this period.
When a woman with prolactinoma presents with infertility and is proceeding with medical treatment for hyperprolactinemia, the patient is advised to use mechanical (barrier) methods of contraception until her menstrual cycles resume and the first few cycles have occurred, so that accurate dating of pregnancy can be performed. BEC is the preferred medical treatment in this situation because of its long safety record. The drug can be discontinued after the first skipped period; despite BEC's safety record, this precaution is taken to prevent unwanted fetal exposure to the agent. To date, however, increased rates of spontaneous abortion, ectopic pregnancy, or teratogenic effects have not been reported with BEC therapy.[37]
Clinical experience with cabergoline-induced pregnancies in approximately 600 patients suggests no excess risk of miscarriage or fetal malformation.[29]
Most women with microprolactinomas do not show significant increases in tumor size during pregnancy. Tumor progression rates of 1-5% have been reported in these patients. In contrast, women with macroadenomas show significant tumor enlargement (15-35%) during gestation, secondary to the hormonal stimulation of lactotrophs.
The treatment of pregnant women with prolactinomas must be tailored to the individual patient. In women with microadenomas, as well as in the subgroup of women who have intrasellar macroadenomas without significant suprasellar or parasellar extension, BEC can usually be safely discontinued upon conception, and the patient can be monitored clinically for symptoms of tumor enlargement. Periodic monitoring of PRL levels and VFs is not usually required in these patients.
In women with larger macroadenomas, a definitive, individualized plan is made only after thorough discussions with the patient. Options include the following:
Transsphenoidal pituitary adenomectomy is the preferred surgical treatment in patients with microprolactinoma and in most patients with macroprolactinoma.[2] A transcranial approach is used only in patients with large extrapituitary extension. A transcranial pituitary tumor resection is more hazardous, being associated with higher mortality and morbidity rates.
A combination of surgery followed by postoperative medical treatment with BEC or one of the other agents is used in patients with incomplete resolution of elevated PRL levels and in persons with residual tumors seen on follow-up imaging studies.
In surgical series of patients with microadenomas, normalization of PRL levels is reported in approximately 70-75% of patients. Recurrence rates of approximately 17% are reported. This surgery is associated with low mortality and morbidity rates (approximately 0.3% and 0.4%, respectively).
Data from a tertiary center indicate an initial cure rate of approximately 90% and a recurrence rate of 16% for microprolactinomas.[38] However, results vary with the experience of the neurosurgeon and the duration of follow-up. Complications include hypopituitarism, bleeding, cerebrospinal fluid rhinorrhea, and diabetes insipidus (see Complications).
In patients with macroprolactinomas, normalization of the PRL level occurs initially in approximately 30% of patients, and the recurrence rate is about 15-20%. Mortality and morbidity rates are less than 1% and 6%, respectively.
Indications for surgery are as follows:
A retrospective study of male patients by Andereggen et al indicated that in men with prolactinomas, impaired bone density remains a problem even after medical (DA agonist) or surgical treatment. The two types of therapy each successfully controlled hyperprolactinemia and hypogonadism. However, at median long-term follow-up (63 mo), bone density pathology was found in 37% of patients, being high in both the medical and surgical cohorts, compared with 27% at baseline.[39]
Mass effects of the tumor may cause VF defects (and blindness), cranial nerve palsies, hydrocephalus, apoplexy (from hemorrhage/infarction into the tumor),[7] and hypopituitarism (from compression of surrounding pituitary cells).
The effects of prolonged, untreated hyperprolactinemia can include hypogonadism, infertility, and osteoporosis.
No long-term complications have been reported with medical treatment. Adverse effects of treatment are discussed in Medical Care and Medication.
The mortality rate for transsphenoidal surgery is 0.27% for microadenomas and 0.86% for macroadenomas. The rate is higher in patients undergoing transcranial surgery and in patients who have been previously been treated with other modalities (~2.5%).
Morbidity includes cerebrospinal fluid rhinorrhea, diabetes insipidus (transient or permanent), meningitis, stroke, visual disturbances, and hypopituitarism (cumulative incidence rate of 2% for microadenomas and up to 14% for macroadenomas).
The major complication is hypopituitarism. It occurs in 33-70% of patients; the incidence increases with the length of follow-up.
Less common complications include damage to the optic nerve/chiasm, seizures, vascular injury, and CNS malignancy.
For patients receiving medical treatment, attempts should be made to continue maintenance treatment at the lowest effective dose to maintain PRL in the normal range. If a decision is made to withdraw medical treatment, especially in microprolactinoma patients, PRL levels and radiologic imaging with MRI or CT scanning should be periodically performed to monitor for recurrence and growth of prolactinoma. Medical treatment may be withdrawn cautiously after menopause in microprolactinoma patients, followed by biochemical and radiologic monitoring.[40]
Guidelines published in 2017 by the European Society of Endocrinology on the management of aggressive pituitary tumors and carcinomas include the following[41] :
The drugs that are effective in the treatment of hyperprolactinemia are DA agonists. DA is the primary physiologic inhibitor of PRL secretion; however, DA is not used for treatment, because it does not cross the blood-brain barrier. Therefore, drugs that mimic the action of DA on the lactotrophs are used in the medical management of prolactinoma.
Clinical Context: DOC for prolactinoma. Bromocriptine is the DA-receptor agonist with the longest record of use for hyperprolactinemia.
Clinical Context: Now available in the United States for use in prolactinoma. Cabergoline is a long-acting DA agonist with efficacy and adverse effects that are similar to those of BEC.
Clinical Context: Specific DA-receptor (type 2) agonist with a relatively long duration of action. Quinagolide is not available in the United States.
Salutary effects on inhibition of PRL synthesis and secretion. These agents are also effective for reducing tumor size.[42]