In over one-third of women with hyperprolactinemia, a radiologic abnormality consistent with a microadenoma (<1 cm) is found. Release of pituitary stem cell growth inhibition via activation or loss-of-function mutations results in cell cycle dysregulation and is critical to the development of pituitary microadenomas and macroadenomas. Microadenomas are monoclonal in origin. Genetic mutations are thought to release stem cell growth inhibitors and result in autonomous anterior pituitary hormone production, secretion, and cell proliferation. Additional anatomic factors that may contribute to adenoma formation include reduced dopamine concentrations in the hypophyseal portal system and vascular isolation of the tumor or both. Recently, the heparin-binding secretory-transforming (HST) gene was noted in a variety of cancers and in prolactinomas (288). Patients with microadenomas can be reassured of a probable benign course, and many of these lesions exhibit gradual spontaneous regression (289,290).
Both microadenomas and macroadenomas are monoclonal in origin. Pituitary prolactinomas and lactotrope adenomas are sparsely or densely granulated histologically. The sparsely granulated lactotrope adenomas have trabecular, papillary, or solid patterns. Calcification of these tumors may take the form of a psammoma body or a pituitary stone. Densely granulated lactotrope adenomas are strongly acidophilic tumors and appear to be more aggressive than sparsely granulated lactotrope adenomas. Unusual acidophil stem cell adenomas can be associated with hyperprolactinemia, with some clinical or biochemical evidence of growth hormone excess.
Microadenomas rarely progress to macroadenomas. Six large series of patients with microadenomas reveal that, with no treatment, the risk of progression for microadenoma to a macroadenoma is only 7% (291). Treatments include expectant, medical, or, rarely, surgical therapy. All affected women should be advised to notify their physicians of chronic headaches, visual disturbances (particularly tunnel vision consistent with bitemporal hemianopsia), and extraocular muscle palsies. Formal visual field testing is rarely helpful, unless imaging suggests compression of the optic nerves.
Autopsy and radiographic series reveal that 14.4% to 22.5% of the US population harbor microadenomas, and approximately 25% to 40% stain positively for prolactin (292). Clinically significant pituitary tumors requiring some type of intervention affect only 14 per 100,000 individuals (292)
Expectant Management In women who do not desire fertility, expectant management can be used for both microadenomas and hyperprolactinemia without an adenoma while menstrual function remains intact. Hyperprolactinemia-induced estrogen deficiency, rather than prolactin itself, is the major factor in the development of osteopenia (293). Therefore, estrogen replacement with typical hormone replacement regimens or hormonal contraceptives is indicated for patients with amenorrhea or irregular menses. Patients with drug-induced hyperprolactinemia can be managed expectantly with attention to the risks of osteoporosis. In the absence of symptoms of pituitary enlargement, imaging may be repeated in 12 months, and if prolactin levels remain stable, less frequently thereafter, to assess further growth of the microadenoma.