Pathophysiology

Microscopic examination of clinically nonfunctioning tumors reveals a spectrum of structural differentiation, from those with well-developed endoplasmic reticulum and Golgi complexes to those with poorly developed cytoplasmic organelles. The latter are often classified as null cell tumors or oncocytomas. In most cases, electron microscopic studies of clinically silent tumors reveal the presence of small secretory granules, suggesting that at least a small amount of each of the several hormones is produced by these tumors (2).

From: Management of Pituitary Tumors: The Clinician's Practical Guide, Second Edition Edited by: M. P. Powell, S. L. Lightman, and E. R. Laws, Jr. © Humana Press Inc., Totowa, NJ

Further in-vivo and in-vitro studies of nonfunctioning pituitary adenomas reveal that most do produce pituitary hormones, in most cases one or more of the pituitary gonadotropins (follicle stimulating hormone [FSH] and luteinizing hormone [LH]) (2-4). The most common hormone produced is FSH, with production of LH or the a-subunits of FSH and LH being less common. Production of these hormones from nonfunctioning pituitary tumors can sometimes be inferred by careful interpretation of basal serum hormone levels. For example, suppressed LH and elevated FSH levels in a patient with a known pituitary tumor indicates an FSH-secreting tumor, because almost all other causes of elevated FSH levels are accompanied by elevated LH levels. In other cases, measurement of the hormones during various stimulation tests reveals abnormal responses that indicate tumoral secretion of these hormones (5). Pathologic analysis of nonfunctioning tumors often shows immunostaining for FSH (3-subunit, LH p-subunit, and/or a-subunit, and in situ hybridization shows the presence of gonadotropin subunit mRNA species (6,7). Finally, most nonfunctioning tumors produce intact gonadotropins and/or gonadotropin subunits when placed in cell culture (6,8,9). Serum hormone levels, immuno-cytochemical staining intensity, mRNA levels, and hormone production in cell culture are not always well correlated in these tumors, illustrating the difficulty in preoperative diagnosis (10).

There are several reasons why these tumors appear nonfunctioning, even though they usually make at least one of the pituitary hormones. The first reason is that FSH and LH excess, unlike the pituitary hormones listed in the first paragraph, do not usually cause any specific symptoms, although rare exceptions exist. For example, a small subgroup of men with FSH-secreting tumors may present with testicular enlargement caused by FSH-induced hypertrophy of the seminiferous tubules. As another example, men rarely have elevated testosterone levels attributable to LH secreting tumors. The second reason is that often only the a- or p-subunits of the hormone are produced, and the uncombined subunits are not active. The third reason is that the hormones are often only secreted into the blood in small amounts, and, therefore, blood levels are often normal.

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