Prolactinomas are the most common hormone-secreting pituitary adenomas, comprising 40% of all pituitary tumors. Prolactinomas present a unique challenge for clinicians, as these tumors are amenable to either medical or surgical treatments based on patients’ comorbidities, tolerance to medical treatment, and the response of tumors to medical treatment. Rare prolactinomas that are unresponsive to either medical or surgical treatment modalities may be responsive to radiation therapy. This article reviews the recent advancements in the management of prolactinomas.
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Prolactinomas are the most common endocrine active adenomas, comprising 40% of pituitary tumors.
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Prolactinomas present a unique challenge for clinicians given the relatively comparable efficacy of medical management versus transsphenoidal surgery.
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A full endocrine laboratory panel should be obtained, especially for macroprolactinomas, as stalk compression can cause hypopituitarism.
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Small, asymptomatic prolactinomas may be observed with close hormonal and radiographic monitoring, whereas symptomatic prolactinomas require treatment.
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Dopamine agonists have become the standard treatment for symptomatic prolactinomas, including macroprolactinomas causing mass-effect symptoms such as visual loss.
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Although most patients with prolactinomas respond to medical therapy, 10% to 20% do not respond to dopamine agonist therapy in terms of prolactin normalization, and may require surgery.
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Transsphenoidal surgery is recommended if (1) the tumor is cystic, (2) inadequate prolactin reduction or tumor growth occurs despite high doses of dopamine agonists, (3) a female patient is planning pregnancy, (4) there is intratumoral hemorrhage with mass effect or apoplexy, (5) the patient presents with rapid visual loss or rapid visual loss occurs on dopamine agonist therapy, or (6) the patient opts for surgical resection rather than medical management.
Introduction
Pituitary tumors represent 10% to 15% of primary intracranial neoplasms, of which more than 90% are benign pituitary adenomas with World Health Organization grade I. Among endocrine active adenomas (EAAs), prolactinomas are the most common, comprising 40% of pituitary tumors. One study, for example, determined that among 46 pituitary macroadenomas found incidentally, 15% were prolactinomas based on laboratory evaluation. Given that autopsy and imaging studies suggest that pituitary tumors are up to 700 times more prevalent (16.7%, or 1 out of 6 people in the general population) than suggested by registry studies, prolactinomas can be a large component of practice for pituitary neurosurgeons and neuroendocrinologists.
Prolactinomas present a unique challenge for clinicians given the relatively comparable efficacy of medical management versus transsphenoidal surgery. In fact, currently prolactinomas are the only brain tumors for which remission, defined as biochemical and radiographic remission in an endocrine active tumor, can be achieved by medical therapy alone. After initial studies proving the efficacy of dopamine agonists as medical therapy for prolactinomas, these medications came to be viewed by many as the first-line therapy for prolactinomas. Over the years, however, several indications have arisen for surgery to treat prolactinomas. The surgical approach to prolactinomas is typically via a transseptal transsphenoidal corridor achieved through microscopic or endoscopic exposure. This article reviews the recent advancements in medical and surgical management of prolactinomas.
Clinical findings of prolactinomas
Symptoms Associated with Prolactinomas
Prolactinomas are the most common EAAs, comprising 40% of pituitary tumors. Symptoms associated with prolactinomas are due to 2 factors: (1) the endocrine effects of prolactin oversecretion and (2) the mass effect on the surrounding structures. Endocrine symptoms include decreased libido, galactorrhea, gynecomastia, amenorrhea in females, and infertility. Because amenorrhea is readily detected in women and decreased libido is often not reported by men, women more often present with microprolactinomas whereas men often present with macroprolactinomas. The prevalence of prolactinomas is generally higher is women as well, possibly because endocrine symptoms are more easily detected in women than in men. Asymptomatic microprolactinomas grow slowly in general and may not require treatment, as only 9 of 139 (7%) women in 6 studies with microprolactinomas had tumor growth during untreated follow-up averaging 8 years.
Patients with large macroprolactinomas, however, may present with symptoms of mass effect, including bitemporal hemianopsia caused by suprasellar extension with compression of the optic chiasm ( Fig. 1 ), headache potentially attributable to stretching of the nearby dura or diaphragm sella, hypopituitarism caused by compression of portal vessels, the pituitary stalk, or the pituitary gland, and cranial neuropathies resulting from parasellar extension with cavernous sinus invasion. Hypopituitarism, most often manifesting as hypogonadism, may be present in 43% of patients with macroadenomas. Though acutely reversible, prolonged compression of the optic chiasm can lead to optic-nerve atrophy, permanent visual-field deficits, and decreased visual acuity. Cranial neuropathies may include ptosis, ophthalmoplegia, and diplopia from compression of the cranial nerves III, VI, and IV, in the order of frequency.
Radiological Findings
The radiographic features of prolactinomas are identical to those of other pituitary adenomas, and are best detected on gadolinium-enhanced magnetic resonance imaging (MRI). Prolactinomas may be isointense or slightly hypointense compared with the pituitary gland on T1-weighted images. While pituitary adenomas such as prolactinomas enhance with gadolinium on T1-weighted images, their enhancement is typically less than that of the pituitary gland or the stalk ( Fig. 2 ). A convex outline along the pituitary gland or deviation of the pituitary stalk away from the adenoma may or may not be present.
Diagnostic Investigations
A full endocrine laboratory panel should be obtained, especially for macroprolactinomas, as stalk compression can cause hypopituitarism. For example, large nonfunctioning pituitary adenomas (NFPAs) may mimic the clinical picture of macroprolactinomas by the stalk effect, whereby compressing the portal vessels can inhibit delivery of dopamine from the hypothalamus to pituitary lactotrophs. Dopamine inhibits prolactin release from the pituitary gland and, thus, the stalk effect can lead to excessive release of prolactin, causing large NFPAs to sometimes present with laboratory hyperprolactinemia that is sometimes clinically symptomatic.
In general, the degree of prolactin elevation correlates with tumor size. Most patients with prolactin greater than 150 mg/L have prolactinomas, whereas macroprolactinomas can have levels well above 250 mg/L. In some giant prolactinomas, prolactin levels may be extremely high, saturating the immunoradiometric assays and leading to falsely low levels. Performing assays with diluted serum samples can prevent this “hook effect.”
Differential Diagnosis
The differential diagnosis in a patient with elevated serum prolactin and a pituitary tumor on MRI is prolactinoma versus NFPA with stalk effect. Although serum prolactin may improve or normalize in stalk-effect patients treated medically, the associated NFPA will usually not regress and the associated mass effect will not improve in the way it would with a prolactinoma treated medically. There is a linear correlation between adenoma size and a serum prolactin below which the stalk effect should be suspected and above which prolactinoma should be suspected, but this correlation is not perfect, particularly with cystic adenomas (see Fig. 1 ). Other different diagnoses include other EAAs (adenomas releasing adrenocorticotropin or growth hormones and, rarely, gonadotropins or thyroid-stimulating hormones), hypophysitis, Rathke cleft cyst, craniopharyngioma, meningioma, and metastases.
Clinical findings of prolactinomas
Symptoms Associated with Prolactinomas
Prolactinomas are the most common EAAs, comprising 40% of pituitary tumors. Symptoms associated with prolactinomas are due to 2 factors: (1) the endocrine effects of prolactin oversecretion and (2) the mass effect on the surrounding structures. Endocrine symptoms include decreased libido, galactorrhea, gynecomastia, amenorrhea in females, and infertility. Because amenorrhea is readily detected in women and decreased libido is often not reported by men, women more often present with microprolactinomas whereas men often present with macroprolactinomas. The prevalence of prolactinomas is generally higher is women as well, possibly because endocrine symptoms are more easily detected in women than in men. Asymptomatic microprolactinomas grow slowly in general and may not require treatment, as only 9 of 139 (7%) women in 6 studies with microprolactinomas had tumor growth during untreated follow-up averaging 8 years.
Patients with large macroprolactinomas, however, may present with symptoms of mass effect, including bitemporal hemianopsia caused by suprasellar extension with compression of the optic chiasm ( Fig. 1 ), headache potentially attributable to stretching of the nearby dura or diaphragm sella, hypopituitarism caused by compression of portal vessels, the pituitary stalk, or the pituitary gland, and cranial neuropathies resulting from parasellar extension with cavernous sinus invasion. Hypopituitarism, most often manifesting as hypogonadism, may be present in 43% of patients with macroadenomas. Though acutely reversible, prolonged compression of the optic chiasm can lead to optic-nerve atrophy, permanent visual-field deficits, and decreased visual acuity. Cranial neuropathies may include ptosis, ophthalmoplegia, and diplopia from compression of the cranial nerves III, VI, and IV, in the order of frequency.
Radiological Findings
The radiographic features of prolactinomas are identical to those of other pituitary adenomas, and are best detected on gadolinium-enhanced magnetic resonance imaging (MRI). Prolactinomas may be isointense or slightly hypointense compared with the pituitary gland on T1-weighted images. While pituitary adenomas such as prolactinomas enhance with gadolinium on T1-weighted images, their enhancement is typically less than that of the pituitary gland or the stalk ( Fig. 2 ). A convex outline along the pituitary gland or deviation of the pituitary stalk away from the adenoma may or may not be present.
Diagnostic Investigations
A full endocrine laboratory panel should be obtained, especially for macroprolactinomas, as stalk compression can cause hypopituitarism. For example, large nonfunctioning pituitary adenomas (NFPAs) may mimic the clinical picture of macroprolactinomas by the stalk effect, whereby compressing the portal vessels can inhibit delivery of dopamine from the hypothalamus to pituitary lactotrophs. Dopamine inhibits prolactin release from the pituitary gland and, thus, the stalk effect can lead to excessive release of prolactin, causing large NFPAs to sometimes present with laboratory hyperprolactinemia that is sometimes clinically symptomatic.
In general, the degree of prolactin elevation correlates with tumor size. Most patients with prolactin greater than 150 mg/L have prolactinomas, whereas macroprolactinomas can have levels well above 250 mg/L. In some giant prolactinomas, prolactin levels may be extremely high, saturating the immunoradiometric assays and leading to falsely low levels. Performing assays with diluted serum samples can prevent this “hook effect.”
Differential Diagnosis
The differential diagnosis in a patient with elevated serum prolactin and a pituitary tumor on MRI is prolactinoma versus NFPA with stalk effect. Although serum prolactin may improve or normalize in stalk-effect patients treated medically, the associated NFPA will usually not regress and the associated mass effect will not improve in the way it would with a prolactinoma treated medically. There is a linear correlation between adenoma size and a serum prolactin below which the stalk effect should be suspected and above which prolactinoma should be suspected, but this correlation is not perfect, particularly with cystic adenomas (see Fig. 1 ). Other different diagnoses include other EAAs (adenomas releasing adrenocorticotropin or growth hormones and, rarely, gonadotropins or thyroid-stimulating hormones), hypophysitis, Rathke cleft cyst, craniopharyngioma, meningioma, and metastases.
Management of prolactinomas
With increasing prevalence of pituitary incidentalomas from more frequent imaging for other reasons, such as headaches, trauma, and vertigo, studies delineating the natural progression history of microprolactinomas will become more important for management stratification. The evidence to date suggests that asymptomatic microprolactinomas grow slowly and may not warrant treatment. Only 9 of 139 (7%) women in 6 studies with microprolactinomas had tumor growth during untreated follow-up averaging 8 years. In another study observing 30 women with hyperprolactinemia for an average of 5.2 years, one-third (10 of 30) of patients had a decrease in prolactin levels during the observation period. Thus, small, asymptomatic prolactinomas may be observed with close hormonal and radiographic monitoring, whereas symptomatic prolactinomas require treatment.
Dopamine Agonist Therapy
Prolactinomas are tumors of lactotrophs, whose production of prolactin is normally inhibited by dopamine from the hypothalamus and enhanced by estrogen. Understanding the regulation of lactotrophs by dopamine has led to the development of drugs to treat prolactinomas. Prolactinoma cells express dopamine D2 receptors which, when activated, cause cell death, decrease cellular metabolism, and decrease prolactin gene synthesis, thereby inhibiting prolactin production and secretion. Furthermore, prolactinoma cell size decreases as well as a result of decreased cytoplasmic, nuclear, and nucleolar areas, with involution of endoplasmic reticulum and Golgi complex, which may be responsible for reduction in tumor size in response to dopamine agonists. Thus, dopamine agonists have been used to treat prolactinomas with great success over the last 4 decades.
Indeed, over the last 25 years dopamine agonists have become the standard treatment for symptomatic prolactinomas, including macroprolactinomas causing mass-effect symptoms such as visual loss. In 1985, a prospective multicenter trial showed that the dopamine agonist bromocriptine, an ergoline derivative that activates dopamine D1 and D2 receptors, normalized prolactin levels in 18 of 27 patients. Tumors decreased in size as early as 6 weeks after administration. Tumor size decreased by more than 50% in 13 patients (46%), 50% in 5 patients (18%), and 10% to 25% in 9 patients (36%). Of note, visual fields improved in 9 of 10 patients who had deficits, confirming that medical treatment can treat tumor mass effect as well. These results with medical therapy resemble those achieved with surgery, and a meta-analysis of 34 series showed that 73.7% of microadenomas and 32.4% of macroadenomas had normal prolactin levels 1 to 12 weeks following surgery. Although a randomized trial directly comparing medical with surgical treatment has not been performed, based on the results of these studies demonstrating comparable efficacy of surgery versus medical therapy, dopamine agonist therapy has replaced surgery as the first-line therapy for prolactinomas, including macroprolactinomas with symptomatic mass effect ( Fig. 3 ).
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