In 60 patients with pituitary adenomas, the serum concentration of the alpha subunit of the glycoprotein hormones (serum alpha) was measured by a sensitive and specific radioimmunoassay. Five patients had markedly elevated serum alpha prior to therapy (range 14.5-23.0 ng/ml). These 5 patients included 2 hyperthyroid men with inappropriately high serum thyrotropin, one of whom also had acromegaly, a man with hyperprolactinemia and elevated cerebrospinal fluid alpha, a postmenopausal woman with low serum gonadotropins and hyperprolactinemia, and a man with central hypothyroidism and hypogonadism. Three of the 5 were restudied after therapy; serum alpha in these three decreased from19.5 to 10.6, 23.0 to 2.0, and 17.0 to 12.0 ng/ml. Alpha in these 3 patinets' serum eluted similarly to normal pituitary alpha by gel chromatography. The other 55 patinets, including twenty with acromegaly, fifteen with galactorrhea, and two with Nelson's syndrome, had serum alpha.less than 0.5-5.0 ng/ml. In addition, 22 patients with "empty sella" syndrome (no pituitary tumor) had alpha less than 0.5-5.0 ng/ml. Normal men and premenopausal women had serum alpha concentrations of less than 0.5-2.5 ng/ml; normal postmenopausal women, 1.0-7.0 ng/ml; and patients with primary hypothyroidism, 0.7-9.0 ng/ml. The decreased alpha response to thyrotropin and luteinizing hormone-releasing hormones (TRH and LHRH) implied a relative autonomy of pituitary tumor alpha secretion; the mean alpha increment in the 5 patients with elevated serum alpha was 15% after TRH administration and 10% after LHRH. Normal individuals and patients with primary hypothyroidism demonstrated greater mean per cent alpha increments after TRH or LHRH. In certain patients with an enlarged sella turcica, an elevated serum alpha with little or no increase in secretion after TRH and LHRH may suggest the presence of pituitary tumor.