Prolactinoma Treatment & Management

Treatment is indicated if mass effects from the tumor and/or significant effects from hyperprolactinemia are present. ^{[10, 27]}

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:

Medical treatment

Bromocriptine (BEC) is generally considered to be the agent of choice in the treatment of prolactinomas because of its long track record and safety. As a DA agonist, it decreases the synthesis and secretion of PRL. ^[11] 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. ^[28]

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. ^[29] The only problem is cost. Side effects are somewhat fewer than with BEC and include headache, nausea, postural hypotension, and fatigue. ^[30]

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. ^[31]

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. ^[32]

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.

Dopamine agonist–resistant prolactinomas (DARPs)

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. ^[33] 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. ^[34]

In those patients with DARPs having persistent hyperprolactinemia despite surgical debulking, with or without radiotherapy, temozolomide, a chemotherapeutic alkylating agent, has been recommended. ^[12] Several case reports have shown temozolomide to reduce prolactin level and control tumor growth. ^{[35, 36]} Despite this, treatment of malignant prolactinomas is difficult, and survival is approximately one year. ^[37]

Radiation treatment

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). ^[38]

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.

Pregnancy and prolactinoma

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. ^[39]

Clinical experience with cabergoline-induced pregnancies in approximately 600 patients suggests no excess risk of miscarriage or fetal malformation. ^[31]

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:

• Discontinuation of BEC at conception and careful monitoring of PRL levels and VFs, with or without MRI scan evidence of tumor enlargement

• Prepregnancy transsphenoidal surgery with debulking of the tumor, with the resultant risk of complications (see Complications)

• Continuation of BEC throughout gestation, with the theoretical risk to the fetus

Transsphenoidal pituitary adenomectomy is the preferred surgical treatment in patients with microprolactinomas and in most patients with macroprolactinomas. ^[3] 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. ^[40]  Similarly, a systematic review and meta-analysis by Zamanipoor Najafabadi et al found that in patients with microprolactinomas, the rate of long-term remission after transsphenoidal surgery was 83%, compared with 36% after withdrawal from dopamine (DA)-agonist therapy. ^[41] 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:

• Women who have a microadenoma, desire pregnancy, and cannot tolerate BEC should undergo surgical treatment.

• Patients who do not wish to take BEC or one of the other drugs long-term should be considered for surgical treatment.

• Patients who do not respond to medical treatment or those who show progression after an initial response to medical treatment should receive surgical treatment.

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. ^[42]

A study by Penn et al indicated that in patients who undergo transsphenoidal surgical resection for prolactinomas, a prolactin level of over 7.6 ng/mL on postoperative day 1 predicts that biochemical control will not be achieved through resection alone. The investigators found the sensitivity and specificity of this prediction to be 79% and 77%, respectively. In addition, surgical cure was achieved in none of the study’s patients with a preoperative prolactin level of greater than 500 ng/mL, while a preoperative level of more than 1000 ng/mL seemed inconducive to biochemical control even with postoperative DA agonist therapy. ^[43]

Neurosurgeon

Complications of untreated prolactinoma

Mass effects of the tumor may cause VF defects (and blindness), cranial nerve palsies, hydrocephalus, apoplexy (from hemorrhage/infarction into the tumor), ^[9]  and hypopituitarism (from compression of surrounding pituitary cells).

The effects of prolonged, untreated hyperprolactinemia can include hypogonadism, infertility, and osteoporosis.

Complications of the treatment of prolactinoma

No long-term complications have been reported with medical treatment. Adverse effects of treatment are discussed in Medical Care and Medication.

Complications of pituitary surgery

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).

Complications of radiation treatment

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. ^[44]