Contemporary Management of Prolactinomas
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Neurosurg Focus 16 (4):Article 2, 2004, Click here to return to Table of Contents Contemporary management of prolactinomas JAMES K. LIU, M.D., AND WILLIAM T. COULDWELL, M.D., PH.D. Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, Utah Prolactin-secreting pituitary adenomas—prolactinomas—are the most common type of functional pituitary tumor. Treatment of hyperprolactinemia is indicated because of the consequences of infertility, gonadal dysfunction, and osteoporosis. Making the correct diagnosis is important because the first line of therapy is medical management with dopamine agonists. Medical therapy is effective in normalizing prolactin levels in more than 90% of patients, but long- term treatment may be required in some patients. Transsphenoidal surgery is usually indicated in those patients in whom medical therapy fails or cannot be tolerated, or in patients who harbor microprolactinomas. In experienced hands, a hormonal and oncological cure can be achieved in more than 90% of patients after transsphenoidal removal of microprolactinomas with minimal risks. Thus, surgery may be an option for microprolactinomas in a young patient who desires restoration of fertility and avoidance of long-term medical therapy. The authors review the diagnosis and management of prolactinomas, including medical therapy, surgical therapy, and stereotactic radiosurgery. KEY WORDS • prolactinoma • pituitary tumor • transsphenoidal approach • bromocriptine • cabergoline Prolactin-secreting adenomas (prolactinomas) account sensitive diagnostic hormone assays, neuroimaging tech- for approximately 30% of pituitary adenomas and 50 to niques, pharmacological therapies, microsurgical and 60% of functional pituitary tumors.149 They are the most endoscopic techniques, and stereotactic radiosurgery. common type of functioning pituitary tumor and are sec- Making the correct diagnosis of prolactinoma is critical ond in frequency to nonfunctioning adenomas in overall to implementing proper therapy. Pharmacological thera- incidence.145 One published estimate of their prevalence is py with dopamine agonists remains the mainstay of 100 cases per 1 million persons;21 however, based on the treatment;8,94,95,144 however, there may be a role for surgi- results of a recent metaanalysis of the literature, one may cal removal in some instances, especially in the case infer that this may be a gross underdiagnosis. According of microprolactinomas.1,31,149 In this paper we will dis- to this metaanalysis, MR imaging and histological exami- cuss current management strategies for patients with pro- nations demonstrate that approximately 17% of patients lactinoma. harbor a microadenoma; one third of these tumors stain positive for prolactin, which indicates the potential for secretion in a large number of incidental adenomas (W. CLINICAL MANIFESTATIONS OF T. Couldwell, unpublished observations). Prolactinomas PROLACTINOMAS commonly cause reproductive and sexual dysfunction; Patients with prolactinomas can present with the clin- macroadenomas can cause local mass effect, resulting in ical sequelae of hyperprolactinemia, endocrine dysfunc- visual compromise, cavernous sinus compression, and hy- 91,92,95,98,145 tion, local mass effect, and/or pituitary apoplexy (Table 1). popituitarism. The objectives for treatment of The biological effects of hyperprolactinemia work pre- hyperprolactinemia due to prolactinomas are to normalize dominantly on the gonadal axis and on breast tissue.9,12 the hyperprolactinemic state, preserve residual pituitary Adult patients in their reproductive years who harbor a function, reduce tumor mass, and prevent disease re- prolactinoma have an impairment of the gonadal axis be- currence. cause of the central inhibitory effects of hyperprolactine- Our understanding of the pathogenesis, clinical presen- mia on hypothalamic production of gonadotropin-releas- tation, and optimal management strategies of prolactino- ing hormone. This results in hypogonadism and infertility. mas is continually evolving. Significant advances in the In premenopausal women, hyperprolactinemia may not be last few decades have contributed to the contemporary detected until after discontinuation of an oral contracep- diagnosis and management of prolactinoma, including tive regimen.2 The signs and symptoms of hypogonadism in children and postmenopausal patients, however, are clinically absent.43,88,122 Adolescents can present with delay Abbreviation used in this paper: MR = magnetic resonance. or failure of sexual/reproductive development.5,17,26,41,90 Neurosurg. Focus / Volume 16 / April, 2004 1 Unauthenticated | Downloaded 09/26/21 09:10 PM UTC J. K. Liu and W. T. Couldwell TABLE 1 the flow of cerebrospinal fluid, resulting in hydro- Clinical manifestations of prolactinomas cephalus. An apoplectic hemorrhage and/or infarction into a pro- hyperprolactinemia lactinoma (pituitary apoplexy) can cause rapid enlarge- amenorrhea (female patients) ment of the tumor, resulting in hypopituitarism and acute galactorrhea (female patients) 80,83 infertility compression of the sellar and parasellar structures. decreased libido Clinical signs and symptoms include sudden onset of impotence (male patients) headache, nausea, vomiting, diplopia, and visual impair- osteoporosis ment. Headache, the most common symptom, is often de- delayed puberty (adolescents) scribed as excruciating and sudden in onset and is fre- mass effect quently associated with nausea and vomiting. When these headaches symptoms are accompanied by meningeal irritation, neck visual acuity & field impairment stiffness, and photophobia from a hemorrhage breaking cranial nerve palsies hypothalamic impairment into the subarachnoid space, the clinical picture may hydrocephalus mimic an aneurysmal subarachnoid hemorrhage. Pituitary hypopituitarism apoplexy often occurs in patients with no history sugges- pituitary apoplexy tive of a pituitary tumor and may represent the first defi- nite indication that a pituitary tumor is present. Women commonly present with galactorrhea, amenor- DIFFERENTIAL DIAGNOSIS rhea, and infertility. Approximately 5% of women with primary amenorrhea and 25% of women with secondary The diagnosis of prolactinoma requires that other caus- es of hyperprolactinemic states and other mass lesions amenorrhea (excluding pregnancy) have a prolactino- 9,12,91 ma.154 When galactorrhea accompanies amenorrhea in in the sellar and parasellar region are ruled out. The women, the incidence of a prolactinoma increases to 70 to cause of hyperprolactinemia can be physiological, phar- 80%.51 Galactorrhea is present in 50 to 80% of women macologically induced, or pathological (Table 2). A care- with hyperprolactinemia.116,117,137 Although prolactinomas ful medical history including a list of current medications, are found to be distributed equally between men and results of a physical examination and routine chemical women at autopsy, women are four times more likely to become symptomatic than men. Women generally pre- sent earlier in the course of the disease and with smaller TABLE 2 tumors (mostly microprolactinomas) at the time of di- Causes of hyperprolactinemia agnosis. In contrast, men commonly present with larger tumors (mostly macroprolactinomas), which cause local physiological mass effect, and symptoms of visual loss, cranial nerve pregnancy 17 breast feeding (suckling reflex) dysfunction, and/or hypopituitarism. Galactorrhea is ex- stress tremely rare in men and the hypogonadal manifestations exercise of decreased libido and impotence are often not recog- pharmacological nized as a sign of hyperprolactinemia. Approximately 2% neuroleptic medication (phenothiazines, haloperidol) of all men with impotence have a prolactinoma.154 Be- atypical antipsychotic medications (clozapine, risperidone) cause most men attribute their sexual dysfunction to the antidepressant medication (primarily amoxapine and rarely other aging process or to functional causes, the presence of a tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors) prolactinoma is often not evident until the tumor becomes antihypertension medication (␣-methyldopa, reserpine, verapamil) large and produces local mass effect. metoclopramide Untreated hyperprolactinemia can also lead to pre- H-2 blockers (intravenous cimetidine) mature osteoporosis in both sexes due to impairment of sellar/parasellar lesions gonadal function leading to a relative estrogen or testos- prolactinomas terone deficiency.51,57,60,73,146 These important, but often nonfunctioning pituitary macroadenomas w/ stalk effect overlooked effects of hyperprolactinemia are additional germinomas arguments for treating patients who may not be concerned craniopharyngiomas about sexual dysfunction. The osteopenia is progressive meningiomas 10 primary empty sella syndrome and correlates with the duration of hypogonadism. Al- lymphocytic hypophysitis though normalization of prolactin levels halts bone loss, histiocytosis X bone density increases to an extent, but does not return to sarcoidosis normal baseline values.40,72,73,115 metastasis Symptoms from mass effect arise from tumor compres- other disease states sion on neighboring structures. Suprasellar extension may primary hypothyroidism cause compression on the optic apparatus, which leads to chest-wall lesion (trauma, surgery, herpes zoster) hypothalamic dysfunction visual deficits. Less commonly, lateral extension into the chronic renal failure cavernous sinus can cause cranial