Definition of prolactinoma
Prolactinomas are pituitary adenomas that produce and secrete prolactin to varying degrees and are almost always benign. Those smaller than 10 mm in size are microadenomas, while those larger than 10 mm are macroadenomas. Occasionally, they are aggressive and locally invade and compress important functional structures. Malignant prolactinomas are extremely rare, can disseminate widely within and outside the central nervous system, and are ineffective in treatment.
Endocrine features
Prolactinomas cause hyperprolactinemia, but hyperprolactinemia does not necessarily mean that a prolactinoma is present; hyperprolactinemia can also occur when hypothalamic dopamine secretion is suppressed by drugs or other causes. Mixed adenomas that secrete growth hormone and prolactin are widely recognized and present as acromegaly combined with hyperprolactin. Prolactin mixed with thyrotropin.
Epidemiology
Approximately 40% of all pituitary tumors are prolactinomas. The age of onset is broad, with reports from 2 to 80 years. They are more commonly seen in women. There is no correlation between the occurrence of prolactinoma and the use of oral contraceptives, but the disease is often noted only after discontinuation of oral contraceptives.
Clinical features
The main clinical manifestation of prolactinoma is due to hyperprolactinemia, which stimulates milk production and also affects gonadal function, leading to various forms of primary (present in children) and secondary menstrual irregularities.
Large prolactinomas that compress other pituitary cells or the pituitary stalk of the hypothalamus can lead to hypopituitarism. Large prolactinomas can produce neurological dysfunction due to tumor occupancy and compression of the optic cross. Neurologic symptoms include headache, visual impairment (which may manifest as quadrant blindness, bilateral temporal hemianopia, or blind spots), and, unless a pituitary stroke occurs, total blindness does not usually result from progressive tumor enlargement.
Men: Hyperprolactinemia usually causes impotence, infertility and hypogonadism in male patients. Male patients often present with large prolactinomas and associated neurological in symptoms, which may be due to delayed recognition of symptoms or different biological characteristics of tumor growth.
Women: The majority of female patients have microadenomas, and approximately 90% of patients present with decreased menstruation or amenorrhea, and nearly 80% have concomitant lactation and anovulatory infertility. Menopausal women do not usually present with these typical symptoms, but are often diagnosed due to the large growth of the tumor producing symptoms of occupational effects such as headache and visual disturbances. However, hyperprolactinemic menopausal women who are on hormone replacement therapy may develop lactation symptoms.
Chronic hyperprolactinemia induced hypogonadism is associated with reduced bone mineral density in both men and women, but to date there have been no reports of increased incidence of pathological fractures in women with hyperprolactinemia. BMD increases after normalization of prolactin, but does not always return to normal levels.
Children: Prolactinomas are rare in children, but a higher proportion of children with prolactinomas are macroadenomas than adults. Clinical presentation is delayed puberty in both sexes, with primary amenorrhea and lactation occurring in girls, while boys have a similar clinical presentation to adult males. Because of the increased incidence of macroadenomas in children with prolactinomas, they are more commonly associated with neurological symptoms.
Causes of hyperprolactinemia other than prolactinoma
Craniopharyngiomas or other saddle or paraspinal occupancies, granulomatous hypothalamic infiltrates, and other large pituitary adenomas can also cause hyperprolactinemia, secondary to impaired hypothalamic dopamine production or impaired dopamine transport by pituitary stalk compression. Chronic renal or hepatic failure is often associated with elevated prolactin, usually due to a decrease in PRL profile. Some primary hypothyroidism is accompanied by mild hyperprolactinemia, the cause of which may be related to stimulation of pituitary prolactin cells by hypothalamic TRH, the exact cause of which is not yet clear. It is worth noting that in primary hypothyroidism careful identification of pituitary enlargement or prolactinoma is required. Other causes of elevated PRL include exercise, diet, stress, chest wall stimulation, and sexual activity.
Drug Factors
Drugs that reduce dopamine secretion or activity can cause hyperprolactinemia. These include gastrofacial, phenothiazine, butyrophenone, risperidone, serotonin reuptake inhibitors (antidepressants; rare), sulpiride, domperidone , and verapamil (extended-release isoptin). Mild hyperprolactinemia with application of sedative psychotropic drugs, caused by several drugs.
The treatment of choice for prolactinoma and hyperprolactinemia is the administration of dopamine agonists such as bromocriptine and capsaicin, which can restore normal levels of prolactin and significantly reduce tumor size, and which have been empirically shown to be effective for both large and small prolactinomas. All dopamine receptor agonists are effective, but pergolide and quinagolide are less commonly used. Patients who are resistant to a specific dopamine agonist or have difficulty tolerating its side effects may be switched to another dopamine agonist.
Treatment of Prolactin Macroadenoma
Dopamine agonist treatment results in normalization of serum PRL and reduction in tumor size in most patients. With dopamine agonists, tumor volume is reduced by more than 25% in 80% of lactosarcomas, and serum PRL is reduced by 50% in almost all patients. In most cases, the tumor size is reduced after 1-2 weeks of administration, but in some patients there is no change for several months. Tumors continue to shrink over several months or even up to a year. It is necessary to review the MRI 2-3 months after starting treatment, and the review interval can be extended thereafter. Several studies have confirmed that anterior pituitary function is restored after tumor volume reduction and ovulatory menstruation resumes in 90% of premenopausal female patients. Dopamine agonist therapy usually restores visual acuity in patients with macroadenoma to about the same level as that achieved by surgical decompression to relieve cross-visual compression, so the presence of visual field defects in prolactin macroadenoma is no longer considered an urgent surgical need.
The goal of treatment is to restore prolactin to normal levels, but many believe that prolactin levels need to be lowered as much as possible in order to minimize the size of the tumor or even make it disappear. It is necessary to start with a lower dose and gradually increase the dose to avoid intolerance and side effects. After tumor reduction, the dose of dopamine agonists can be gradually reduced if PRL levels remain normal. In fact, it has been suggested that keeping PRL levels normal but not low is more effective in restoring reproductive function. After PRL levels have recovered for more than two years and tumor size has decreased by more than 50%, dopamine agonists can be tapered to a lower dose, as lower doses during this period usually maintain stable PRL levels and tumor size. It is important to note that discontinuation of medication for prolactinomegalic adenoma may result in tumor enlargement and recurrence of hyperprolactinemia, so patients with prolactinomegalic adenoma must be closely followed when the medication is tapered or stopped.
Short-term follow-up and prolactin resistance
Prolactin resistance should be considered if the patient does not show the expected improvement on dopamine agonists, and subsequent treatment options include taking the maximum tolerated dose, switching to another dopamine agonist, or considering Surgical resection or radiation therapy may be considered.
Surgery and radiation therapy for prolactinoma
1. Transsphenoidal surgery
The use of transsphenoidal surgery to achieve a long-term cure is not reliable, and recurrence of hyperprolactinemia is common. The success rate of microadenoma surgery is about 75%, and the cure rate of macroadenoma is even lower. Surgery is not curative when tumor growth extends into the cavernous sinus. Hyperprolactinemia recurs in about 20% of those who initially return to normal. Approximately 10% of patients require surgical treatment due to dopamine agonist resistance or lack of improvement in visual field defects. Other indications for surgery include: macroadenoma stroke with neurological signs; cystic prolactinomatous macroadenoma (tumors that are often difficult to shrink with dopamine agonist therapy) resulting in neurological symptoms; and difficulty tolerating dopamine agonists. The neurosurgeon should provide the patient with a comparison of the results of surgery versus dopamine agonists to discuss whether surgery is indicated, and if the patient prefers surgery, this may also be an indication for surgery.
2. Radiation therapy
External radiation therapy is rarely used for the treatment of prolactinomas and has a high incidence of major complications, including pituitary hypofunction, optic nerve damage, neurological disorders, high risk of stroke, and secondary brain tumors. Therefore, radiation therapy cannot be the treatment of choice and should only be used in patients in whom dopamine agonists are ineffective and cannot be cured surgically, or in those with very rare malignant prolactinomas.
3. Treatment of malignant prolactinoma
Malignant prolactinomas can only be treated with surgery or radiation. These tumors may initially present as resistant prolactinomas (dopamine agonist resistance) or as serum PRL levels that are disproportionate to the size of the tumor. However, it is important for the physician to be clear that this tumor has no typical clinical presentation other than failure of dopamine agonist therapy and recurrence after surgery. Often, the pathologic profile is not noteworthy and the mild elevation of the mitotic index is nonspecific. In true malignant prolactinomas, the first characteristic manifestation may be tumor extension to other sites of intracranial discontinuity or metastasis to extracranial sites. Experience with the management of malignant prolactin is extremely limited, with surgery or radiation therapy providing only temporary relief and chemotherapy providing little or no effect. These tumors are invariably fatal, but fortunately rare.
4. Pregnancy and Prolactinoma
For various reasons, women with prolactinoma who are pregnant or wish to become pregnant need to be guided through the process by an (endocrinologist) physician. During pregnancy, prolactinomas can increase in size considerably and bring about visual impairment, on the other hand, serum prolactin values do not really reflect the size of the tumor. In addition, dopaminergic drugs can cross the placental barrier and their effects on the fetus need to be carefully considered. There are four main issues to consider between pregnancy and prolactinoma: hyperprolactinemia and pregnancy; safety of dopamine agonists; tumor growth; and lactation.
5. Hyperprolactinemia and Conception
Female patients should be aware that when dopamine agonist therapy is initiated, the return of the ovulatory cycle and the ability to conceive may be rapid (pregnancy may occur even before the first normal menstrual period occurs). For this reason, it is generally recommended that the patient apply the contraceptive device promptly after starting treatment, with menstruation as a more definitive indicator. If the patient intends to become pregnant, she should plan to conceive after the PRL has decreased to normal and the tumor has significantly decreased in size, in order to reduce the risk of visual cross-compression due to tumor enlargement during pregnancy. For infertile women who have difficulty tolerating dopamine agonists or who refuse to take medication, transsphenoidal tumor resection is an option.
6. Safety of dopamine agonists
Worldwide, a significant number of patients take bromocriptine for prolonged periods of time during and after conception, and the incidence of miscarriage, ectopic pregnancy, and other congenital malformations in infants is not higher than in the normal population of patients taking the drug during pregnancy. According to the literature, the situation is similar for patients taking cabergoline, but the number of studied cases is still smaller than for bromocriptine. According to animal model studies, no teratogenicity has been found with the application of cabergoline during pregnancy. In contrast, there is little experience with the use of pergolide and quinagolide in patients planning to become pregnant, and their use is not recommended in this setting.
Although the application of bromocriptine and cabergoline has not caused additional problems, it is best to minimize fetal exposure factors to these drugs during pregnancy. Teratogenicity from various drugs or other factors occurs most often during the first trimester of pregnancy, which also happens to be the period of least regrowth of prolactinomegal adenoma after discontinuation of the drug in pregnant women, and therefore patients are advised to discontinue bromocriptine or cabergoline after cessation of menstruation and a positive pregnancy test. The effects of cabergoline are long lasting and PRL levels can remain suppressed for up to 120 days after discontinuation.
7.Tumor growth
The risk of tumor enlargement during pregnancy is not higher than 2% for prolactin microadenoma, so such patients can safely discontinue the drug after pregnancy is confirmed. Patients who have severe headache and vision loss need to be reviewed promptly without continuous monitoring of PRL levels. Symptomatic tumor enlargement occurs in about 20-30% of women with macroadenoma during pregnancy. For these patients, it is recommended that dopamine agonists be discontinued after pregnancy is confirmed and followed closely, or that they continue to be taken throughout pregnancy. If visual field loss or progressive headache occurs, review MRI plain (no CT) for changes in tumor size and resume dopamine agonists if the tumor size increases significantly. To prevent the possibility of tumor enlargement during pregnancy in women with prolactinomegalic adenoma, reduction (partial removal of the tumor) before pregnancy is not a good option, and treatment with medication during pregnancy may be less damaging than surgery. If the tumor grows again after discontinuation of medication in pregnant women, if the tumor size is not controlled by reapplication of dopamine agonists, delivery may be timely if the pregnancy is long enough, or transsphenoidal surgery may be performed.
8.Lactation
Women who breastfeed their infants should not continue to take dopamine agonists, as dopamine agonists can lower serum PRL levels and affect lactation. There is no evidence that breastfeeding can lead to tumor enlargement.
9. Long-term follow-up
The course of dopamine agonist therapy should be at least 1 year. It is important to note that some patients maintain sustained tumor shrinkage after several years of dopamine agonist therapy. There is little evidence to determine successful discontinuation, but some studies suggest that dopamine agonists can be safely discontinued if prolactin levels remain normal over time and MRI reveals no tumor. Patients with normal PRL levels and significant tumor size reduction after more than 3 years of dopamine agonist therapy may attempt to discontinue the medication, but such patients should be closely followed and medication should be resumed as soon as prolactin rises again and tumor size increases.