Endocrine-active adenomas result in characteristic syndromes caused by hypersecretion or dysregulated secretion of a hormone by the pituitary tumors. Endocrine-inactive adenomas and large endocrine-active adenomas can present with symptoms associated with anterior pituitary gland compression, resulting in hypopituitarism, or with elevation of the optic chiasm, resulting in bitemporal hemianopia (chiasmatic syndrome).
Progressive compression of the anterior lobe causes progressive loss of glandular function with GH, FSH, and LH being affected early, and TSH and ACTH affected later. The earliest symptom in adult males is loss of libido or infertility and in premenopausal women, oligomenorrhea or amenorrhea. Central hypogonadism can be caused by primary compression of the pituitary gland, causing diminished LH/FSH secretion, or by loss of tonic inhibition of prolactin secretion, resulting in hyperprolactinemia (stalk effect) and subsequent physiologic suppression of gonadotropins. Diabetes insipidus, a result of direct hypothalamic or pituitary stalk involvement, is rarely caused by pituitary adenomas. As pituitary adenomas enlarge, they grow outside the sella turcica and result in suprasellar extension. This elevates the optic chiasm and will lead to distortion of the decussating nasal fibers, causing bitemporal hemianopia. With progressive compression of the optic chiasm and nerves, decreased visual acuity can occur, eventually leading to blindness. Endocrine-inactive adenomas grow slowly and thus present when they are relatively large, particularly in males and postmenopausal women. In rare cases, intratumoral hemorrhage or infarction may occur, resulting in a sudden increase in tumor size and intrasellar pressure (pituitary apoplexy). With apoplexy, patients present with severe headaches, sudden vision loss (including acute blindness), and panhypopituitarism.
The sudden loss of pituitary function can result in addisonian crisis, with patients developing headaches, nausea, electrolyte abnormalities, and hypotension. In cases of pituitary apoplexy, immediate correction of the hypocortisolemia and surgical decompression of the optic nerves to preserve visual function is necessary.
Elevated growth hormone levels result in acromegaly after puberty (when the epiphyseal plates have fused) or gigantism prior to puberty. The clinical findings of an enlarged protruding jaw (macrognathia)—with associated overbite, separation of the teeth, enlarged tongue (macroglossia), enlarging hands or feet, coarse facial features, arthralgias, skin tags, hyperhidrosis, hirsutism, deepening of the voice, and nerve entrapment syndromes—are common in acromegaly. Cardiovascular disease with left ventricular hypertrophy, hypertension, and diabetes mellitus result in an increased risk of cardiovascular morbidity in patients with acromegaly. There is also a significant increased risk of colonic polyps that mandates colonoscopy in patients with this diagnosis.
Hyperprolactinemia is among the most common of pituitary disorders and may be seen in a variety of medical conditions through different mechanisms. Prolactinomas are primarily diagnosed in young women. Since the hyperprolactinemia can result in primary or secondary amenorrhea early on, these tumors are typically diagnosed as microadenomas. The elevated prolactin causes physiologic suppression of FSH/LH with subsequent hypogonadism and also causes galactorrhea and gynecomastia, hence the syndrome of galactorrhea/amenorrhea in women. In postmenopausal women and men, the hypogonadism is often undiagnosed; thus, these tumors typically present as macroadenomas. Hyperprolactinemia up to 150 ng/dL can also be caused by loss of the tonic inhibition of prolactin secretion (“stalk effect”).
Hypercortisolemia can be due to Cushing’s syndrome (as in adrenal adenomas) or Cushing’s disease. The clinical syndrome is the same, with centripetal fat deposition resulting in moon facies and a buffalo-hump, facial plethora, diabetes mellitus, abdominal striae, hirsutism, osteoporosis, myopathy, and often psychic disturbances including depression. The diagnosis can be confirmed by laboratory testing, MRI imaging, and occasionally inferior petrosal sampling of ACTH levels.
Elevated TSH causes hyperthyroidism and can be associated with thyrotoxicosis and osteoporosis. TSH-secreting adenomas are extremely rare, comprising 1% of pituitary adenomas.
For endocrine-inactive adenomas presenting with hypopituitarism, headaches, or chiasmatic syndrome, an MRI focused on the sella will confirm the diagnosis and extent of tumor involvement. Current MRI with coronal and sagittal views will identify all but the smallest (< 2 mm) intrasellar tumors. Occasionally, an incidental adenoma may be seen on MRI and complete hormonal evaluation will confirm whether the tumor is asymptomatic, as are most endocrine-inactive microadenomas. Other sellar and perisellar masses include a Rathke's cleft cyst, craniopharyngioma, tuberculum sella meningioma, cavernous sinus meningioma, chordoma, or rarely metastatic lesion. The presence of diabetes insipidus would raise the suspicion of a lesion affecting the pituitary stalk such as germ cell tumor, Langerhans histiocytosis X, lymphocytic hypophysitis, or sarcoidosis.
For endocrine-active adenomas, the diagnosis is established by laboratory tests of pituitary hormones and clinical features. Dynamic studies such as the physiologic regulation of hormone secretion can be helpful. In some patients with Cushing's disease, a tumor too small to detect from standard imaging may be present and require further investigation with inferior petrosal sinus sampling. Hyperprolactinemia can result from many causes, including pregnancy, emotional or physical stress, medications (such as phenothiazines, antipsychotics, and certain antidepressants), or hypothyroidism.
Treatment of Pituitary Tumors
The treatment of symptomatic endocrine-inactive adenomas is surgical resection. This is usually accomplished through a transsphenoidal approach. Despite several variations including sublabial, transnasal/transseptal, endonasal, and endoscopic transsphenoidal approaches, all are associated with low morbidity and short hospital stays when performed in experienced centers. The surgical goal is an attempt for complete resection of the tumor with preservation of the remaining normal pituitary gland. In many large adenomas, invasion into the cavernous sinus will preclude a gross total resection. In such cases, radiotherapy may be necessary. With the advent of stereotactic radiosurgery, it is possible to treat residual surgically inaccessible tumors with radiation therapy without sacrificing pituitary function. Although standard fractionated external beam radiotherapy is effective in the treatment of pituitary adenomas, the risk of hypopituitarism remains high. Therefore, in patients with adequate pituitary function, either stereotactic radiosurgery should be utilized when possible or radiotherapy should be deferred until recurrent tumor growth can be documented. Rarely, a transcranial approach may be necessary if the anatomy of the tumor is atypical or the radiographic diagnosis suggests a nonpituitary pathology.
Prolactinomas are the only pituitary adenoma where an effective medical therapy is available. An MRI is imperative before medical therapy is started to assess whether the cause is an endocrine-inactive macroadenoma with stalk effect or a prolactinoma. The use of dopamine analogues such as bromocriptine can normalize the prolactin level, cause shrinkage of the tumor, and prevent future tumor growth while patients receive therapy. With bromocriptine, lifelong therapy is required; however, cabergoline, which is a selective D2 agonist, may have more longer-acting effects.
Currently, patients may undergo withdrawal of cabergoline therapy with close monitoring. In women with large prolactinomas, tumor control during pregnancy may be complicated when medical therapy needs to be halted. For patients with acromegaly who are not cured by surgery, medical therapy with somatostatin analogues can inhibit GH release. Persistent Cushing’s disease may necessitate radiotherapy to control the primary tumor or bilateral adrenalectomy to control the hypercortisolemia.